Active compounds

ABSTRACT

Therapeutically active compounds of the formula: ##STR1## wherein the variables are defined in the specification are provided.

This application is a 371 of PCT/SE92/00190.

FIELD OF THE INVENTION

The object of the present invention is to provide novel compounds, andtherapeutically acceptable salts thereof, which inhibit exogenously orendogenously stimulated gastric acid secretion and thus can be used inthe prevention and treatment of peptic ulcer.

The present invention also relates to the use of the compounds of theinvention for inhibiting gastric acid secretion in mammals includingman. In a more general sense, the compounds of the invention may be usedfor prevention and treatment of gastrointestinal inflammatory diseases,and gastric acid-related diseases in mammals including man, such asgastritis, gastric ulcer, duodenal ulcer, reflux esophagitis andZollinger-Ellison syndrom. Furthermore, the compounds may be used fortreatment of other gastrointestinal disorders where gastricantisecretory effect is desirable e.g. in patients with gastrinomas, andin patients with acute upper gastrointestinal bleeding. They may also beused in patients in intensive care situations, and pre- andpostoperatively to prevent acid aspiration and stress ulceration, Theinvention also relates to pharmaceutical compositions containing atleast one compound of the invention, or a therapeutically acceptablesalt thereof, as active ingredient. In a further aspect, the inventionrelates to processes for preparation of such new compounds, and to theuse of the active compounds for the preparation of pharmaceuticalcompositions for the medical use indicated above.

PRIOR ART

Certain pyrrolo[2,3-b]pyridines have been disclosed in Sally Pak.J.Pharmacol. 86 Vol 2(2) pp 43-36 (1985), Saify, J. Pharm. Univ. Kar.2(2):99-103 (1984), TimPe et al. J. Prakt. Chem. 80 Vol 322(3) pp 517-21(1980) Ogali et al., Indian Journal of Chemistry Vol. 27B, 656-651(1988).

THE INVENTION

It has been found that compounds of the following formula I areeffective as inhibitors of gastric acid secretion. The compounds of theformula I exert this effect by inhibiting the gastrointestinal H⁺ K⁺-ATPase enzyme.

The compounds of the invention are of the following formula I: ##STR2##or a pharmaceutically acceptable salt thereof, wherein X represents##STR3## or --CH₂ --; R¹ represents H, lower alkyl, CH₂ --O--R⁷ halogenphenyl or phenyl substituted with (1-6c) alkyl, (1-6c) alkoxy, (1-6c)acyl, halogen, CF₃, CN, NH₂, NO₂ or (1-6c) alkoxycarbonyl;

R² represents H, lower alkyl, CH₂ CN, ##STR4## halogen, O--R⁸, ##STR5##S--CN, CH₂ OH, CH₂ C.tbd.CH, CF₃,CH₂ NC or NH₂ ; R³ represents H, loweralkyl, CF₃, O--R⁹, NH₂, lower

alkylamino, di-lower alkylamino, halogen, CN, ##STR6## S--R¹⁰ or NHCOR¹⁰; R⁴ and R⁵ which are the same or different represent H lower alkyl, CN,halogen, O--R¹¹, NO₂, NH₂, lower alkylamino, di-lower alkylamino,S--R¹², NHCOR¹³, ##STR7## R⁶, R⁷, R⁸, R⁹, R¹¹, and R¹³ which are thesame or different, represent H or lower alkyl;

R¹⁰ represents lower alkyl or phenyl lower alkyl;

R¹² and R¹⁴ which are the same or different represent lower alkyl;

R¹⁵ represents H, lower alkyl, OH or lower alkoxy; provided that R¹ andR² are not simultaneously H. As used herein, the term "lower" whenapplied to hydrocarbon groups, alkoxy-, alkylamino-, dialkylamino-,alkylthio, alkylsulfinyl-, phenylalkylthio-, phenylalkylsulfinyl,acylamino- or alkoxycarbonyl groups includes straight and branched chainhydrocarbon group having up to 6 carbon atom.

The term halogen includes fluoro, chloro bromo and iodo.

Both the pure enantiomers, racemic mixtures and unequal mixtures of twoenantiomers are within the scope of the present invention. It should beunderstood that all the diastereomeric forms possible (pure enantiomersor racemic mixtures) are within the scope of the invention. Alsoincluded in the invention are derivatives of the compounds of theformula I which have the biological function of the compounds of theformula I.

Depending on the process conditions and the starting materials, the endproducts of the formula I are obtained either in neutral or salt form.Both the free base or acid and the salts of these end products arewithin the scope of the invention.

Acid addition salts of the new compounds may in a manner known per se betransformed into free base using basic agents such as alkali or by ionexchange. The free base obtained may also form salts with organic orinorganic acids. In the preparation of acid addition salts, preferablysuch acids are used which form suitably therapeutically acceptablesalts.

Examples of such acids are hydrohalogen acids, sulfonic acids,phosphoric acid, nitric acid, aliphatic, alicyclic, aromatic orheterocyclic carboxyl or sulfonic acids, such as formic acid, aceticacid, propionic acid, succinic acid, glycolic acid, lactic acid, malicacid, tartaric acid, citric acid, ascorbic acid, maleic acid,hydroxymaleic acid, pyruvic acid, p-hydroxybensoic acid, embonic acid,methanesulfonic acid, ethanesulfonic acid, hydroxyethanesulfonic acid,ethylenesulfonic acid, halogenbensenesulfonic acid, toluenesulfonic acidor naphtylsulfonic acid.

These or other salts of the new pyrrolo[2,3-b]pyridine, as e.g.picrates, may serve as purifying agents of the free bases obtained.Salts of the bases may be formed, separated from solution, and then thefree base can be recovered in higher purity from a new salt solution.

Base addition salts of the new compounds may be transformed into theacid form using inorganic or organic acids, and then reconverted to atherapeutically suitable salt such as sodium and potassium salts byaddition of NaOH and KOH, respectively.

Preferred groups of compounds of the formula I are:

1. Compounds wherein X is ##STR8## or --CH₂ -- and R⁶ is as definedabove

2. Compounds wherein R¹ is lower alkyl, optionally substituted phenyl,CH₂ OR⁷ or halogen and R⁷ is as defined above.

3. Compounds wherein R² is H, lower alkyl, CH₂ C.tbd.CH, CH₂ OH, CH₂ CN,##STR9## CH2NC, NH₂, ##STR10## SCN, halogen or CF₃.

4. Compounds wherein R³ is H, lower alkyl, O--R⁹, NH₂, lower alkylamino,di-lower alkylamino, C.tbd.N, S--R¹⁰, ##STR11## halogen, CF₃ or NHCOR¹⁰and R⁹ and R¹⁰ are as defined above.

5. Compounds wherein R⁴ and R⁵ are the same or different and selectedfrom H, lower alkyl, C.tbd.N, halogen, O--R¹¹, NO₂, NH₂, loweralkylamino, di-lower alkylamino, S--R¹²,

NHCOR¹³, CF₃ or ##STR12## and R¹¹, R¹², R¹³ and R¹⁵ are as definedabove.

More preferred groups of compounds of the formula I are:

1. Compounds wherein X is ##STR13## or --CH₂ --

2. Compounds wherein R¹ is CH₃, C₂ H₅, CH(CH₃)₂, CH₂ CH₂ CH₃, Cl, Br orphenyl

3. Compounds wherein R² is H, CH₃, C₂ H₅, CH₂ CN, ##STR14## F, Cl, Br,SCN, CH₂ OH, CH₂ C.tbd.NCH, CF₃ or CH₂ NC

4. Compounds wherein R³ is H, CH₃, C₂ H₅, CH(CH₃)₂, CH₂ CH₂ CH₃, CF₃,OH, OCH₃, OC₂ H₅, OCH(CH₃)₂, NH₂, NHCH₃, NHC₂ H₅, N(CH₃)₂, N(C₂ H₅)₂, F,Cl, Br, S--CH₃, S--C₂ H₅, ##STR15## or NHCOCH₃.

5. Compounds wherein R⁴ and R⁵ are the same or different and selectedfrom H, CH₃, C₂ H₅, CH(CH₃)₂, F, Cl, Br, OH, OCH₃, OC₂ H₅, OCH(CH₃)₂,NO₂, NH₂, NHCH₃, NHC₂ H₅, N(CH₃)₂, N(C₂ H₅)₂, S--CH₃ or CF₃.

The radical R³ is in position 4, 5 or 6, preferably in position 5 or 6in the compound of Formula I.

The radicals R⁴ and R⁵ are in positions 2, 3, 4, 5 or 6 of the phenylnucleus.

The most preferred compound of the invention is: ##STR16##

Other preferred compounds of the invention are: ##STR17##

PREPARATION

The present invention also provides processes for the manufacture of thecompounds with the general formula I. The compounds may be prepared inthe following way.

A. A compound of the general formula II ##STR18## wherein R¹, R² and R³are as defined above is reacted with a compound of the general formulaIII ##STR19## wherein X, R⁴ and R⁵ are as defined above and Y is aleaving group, such as a halide, tosyloxy or mesyloxy whereby a compoundof the general formula I, wherein X, R¹, R², R³, R⁴ and R⁵ are asdefined above is obtained. It is convenient to conduct this reaction ina solvent. The solvent used for the reaction is preferably a polarsolvent such as acetonitril or dimethyl formamide or an alcohol, e.g.ethanol or isopropanol.

The reaction temperature ranges usually from about 20° C. to about theboiling point of the solvent used, more preferably from about 20° C. toabout 80° C. The reaction time ranges from about 0.1 to about 96 hours.

B. Compounds of the formula I wherein X is CHOH and R¹, R₂, R³, R⁴ andR⁵ are as defined above are prepared by reducing a compound of formula Iwherein X is C═O and R¹, R², R³, R⁴ and R⁵ are as defined above, e.g. byreacting with a reducing agent such as NaBH₄, LiAlH₄ or by catalytichydrogenation.

C. Compounds of the formula I wherein R² is OH and X, R¹, R³, R⁴ R⁵ areas defined above are prepared by reacting a compound of formula Iwherein X, R¹, R³, R⁴ and R⁵ are as defined above and R² is O(1-6C)alkylwith a dealkylation agent such as B(Br)₃ or (CH₃)₃ SiI.

D. Compounds of the formula I wherein X is CHO--R⁶ and R¹, R², R³, R⁴and R⁵ are as defined above are prepared by reacting a compound offormula I wherein X is CHOH and R¹, R², R³, R⁴ and R⁵ are as definedabove with a compound of formula IV

    R.sup.6 --Z                                                IV

wherein R⁶ is as defined above and Z is a reactive esterified hydroxygroup.

E. Compounds of the formula I wherein R⁴ is 2--OH, R⁵ is different fromR⁴, and X R¹, R² and R³ are as defined above are prepared by reacting acompound of formula I wherein X, R¹, R², R³ and R⁵ are as defined aboveprovided that R⁵ is different from R⁴, and R⁴ is 2--O(C₁ -C₆ alkyl) witha dealkylation agent such as B(Br)₃ or (CH₃)₃ SiI.

The compound of the formula I thus obtained is then, if desired,converted to a pharmaceutically acceptable salt.

EXAMPLES Example 1

Preparation of 2-methyl -7- (2-phenylethyl)-pyrrolo[2,3-b]pyridine

A solution of 85 mg (0.64 mmol) of 2-methyl-pyrrolo[2,3-b]pyridine and140 mg(0.76 mmol) of (2-bromoethyl)benzene in 1 ml acetonitrile wasrefluxed for 40 h. The solvent was evaporated and the residue wastreated with ether. The solid that formed was isolated by filtration togive 188 mg (62%) of 2-methyl-7-(2-phenylethyl)pyrrolo[2,3-b]pyridinehydrobromide.

(¹ H-NMR, 500 MHz, CDCl₃) 2.78(s,3H), 3.44 (t, 2H), 5.40(t,2H)6.44(s,1H), 6.97(dd,2H) , 7.08(dd, 1H) , 7.18(m, 3H), 7.31(d, 1H) ,8.17(d, 1H) .

Example 2

3-Chloro-2-methyl-7-(2-phenylethyl)pyrrolo[2,3-b[pyridine hydrobromide

A solution of 28.4 mg (0.17 mmol) of 3-chloro-2-methyl pyrrolo[2,3-b]pyridine and 36 mg (0.2mmol) of (2bromoethyl)benzene in 0.4 ml ofdimethylformamid was heated at 80° C. for 20 h. The solvent wasevaporated. The solid that formed was treated with ethyl acetate andisolated by filtration to give 30 mg (50%) of 3-chloro-2-methyl-7-(2-phenylethyl)pyrrolo[2,3-b]pyridine hydrobromide.

(¹ H-NMR, 500 MHz,CDCl₃) 2.77(s,3H), 3.45(t,2H), 5.40(t,2H),6.95(dd,2H), 7.14(dd, 1H) , 7.2(m, 3H), 7.28(d, 1H), 8.24 (d, 1H).

Example 3

3-Cyanomethyl-2-methyl-7-(2-phenylethyl)pyrrolo[2,3-b]pyridine

A solution of 130 mg (0.76 mmol) of3-cyanomethyl-2-methyl-pyrrolo[2,3-b]pyridine and 150 mg (0.81 mmol) of2-bromoethyl-benzene in 2 ml of acetonitrile was refluxed for 40 h. Thesolvent was evaporated and the crude product was chromatographed onsilica gel with ethyl acetate: methanol: water 100:12:4.Recrystallization from a small amount of ether: petroleumether 1:1 gave53 mg (25%) of3-cyanomethyl-2-methyl-7-(2-phenylethyl)pyrrolo[2,3-b]pyridine.

(¹ H-NMR, 500 MHz, CDCl₃) 2.59 (s, 3H), 3.34(t,2H), 3.83(s,2H),4.84(t,2H), 6.66(dd, 1H) , 7.01 (dd, 2H), 7.07(d, 1H) , 7.23(m, 3H) ,7.94(d, 1H).

Example 4

3 -Methyl-7-(2-phenylethyl)pyrrolo[2,3-b ]pyridine hydrobromide.

A solution of 0.3 g (2.3 mmol) 3-methylpyrrolo[2,3-b]pyridine and 0.5 g(2.7 mmol) (2-bromoethyl)benzene in 10 ml acetonitril was refluxed for72 h. The solvent was evaporated and the solid that formed was treatedwith ether. Recrystalization from ethyl acetate gave 0.2 g (27%) of thetitle compound as a white solid.

(¹ H-NMR, 300 MHz, CDCl₃) 2.35(s,3H), 3.45(t,2H), 5.4(t,2H), 6.9-7.0(m,2H), 7.1(t,1H), 7.2-7.3(m, 3H), 7.4(dd, 1H), 7.55(s,1H) , 8.25(dd, 1H) .

Example 5

2-Hydroxymethyl-3-methyl-7-(2-phenylethyl)pyrrolo[2,3-b]pyridinehydrobromide

A solution of 0.11 g (0.68 mmol) 2-hydroxymethyl-3-methylpyrrolo[2,3-b]pyridine and 0.13 g (7 mmol) (2-bromoethyl)benzene in 5 mlacetonitril was refluxed for 24 h. The solvent was evaporated.Chromatography on silica gel eluting with methylene chloride andmethanol (10:1) gave the desired product. (0.03 g 13%).

(¹ H-NMR, 500 MHz,CDCl₃), 2.35(s,3H), 3.4(t,2H), 4.95(s,2H), 5.1(t,2H),6.95-7.0(m, 2H), 7.05(t,1H), 7.2-7.25(m, 3H), 7.35(dd, 1H) , 8.15(dd,2H) .

Example 6

2-Chloro-3-methyl-7-(2-phenylethyl)pyrrolo[2,3-b]pyridine

A solution of 0.1 g (0.6 mmol) 2-chloro-3-methylpyrrolo-[2,3-b]pyridineand 0.14 g (0.78 mmol) (2-bromoethyl)-benzene in 10 ml acetonitril wasrefluxed 72 h. The solvent was evaporated. The solid that formed wastreated with ether and ethyl acetate and isolated by filtration.Chromatography on silica gel eluting with methylene chloride andmethanol (10:1) gave the desired product. (0.03 g 18% ).

(1H-NMR, 300 MHz,CDCl₃) 2.3(s,3H), 3.35(t,2H), 4.8(t,2H), 6.65(t,1H),6.95-7.0(m,2H), 7.05(dd, 1H), 7.2-7.25(m, 3H), 7.8(dd, 1H).

Example 7

6-Amino-2,3-dimethyl-7-(2-phenylethyl)-pyrrolo[2,3-b]pyridinehydrobromide

A solution of 6-amino-2,3 -dimethyl-pyrrolo [2,3-b]pyridine (1.0 g, 6,2mmol ) and phenethyl bromide (1,7 g, 9,3 mmol ) in 30 ml CH₃ CN wasrefluxed for 48 h. The mixture was allowed to cool and the precipitatewas filtered off. Chromatography on silica gel eluting with methylenechloride and methanol (9:1) gave the desired product (0,1 g, 6%).

(¹ H-NMR, 500 MHz, CDCl₃ +CD₃ OD) 2,10(s,3H), 2,25(s,3H), 3,20(t,2H),4,70(t,2H), 6,60 (d, 1H) , 7,10 (dd, 2H) , 7,15-7,20(m, 3H), 7,75(d,1H).

Example 8

2,3 -Dimethyl-7-phenacylpyrrolo[2,3-b]pyridine.

A solution of 2,3-dimethylpyrrolo[2,3-b]pyridine (146 mg, 1 mmol) andphenacyl chloride (170 mg, 1.1 mmol) in 3 ml CH3CN was refluxed for 4.5h. The mixture was allowed to cool and the precipitated product filteredoff and washed with a small volume of ice cold CCl₄ affording 207 mg(69%) pure title compound as the hydrochloride salt.

(¹ H-NMR, 300 MHz, DMSO-d₆), 2.29(s,3H), 2.42(s,3H), 6.66(s,2H),7.65(m,3H), 7.80(t,1H), 8.11(d,2H), 8.47(d, 1H), 8.62(d, 1H), 13.5(b,1H).

Example 9

3-Chloro-2-methyl-7-phenacylpyrrolo[2,3-b]pyridinehydrochloride

A solution of 200 mg (1.2 mmol) of 3-chloro-2-methylpyrrolo-[2,3-b]pyridine and 204 mg (1,3 mmol) of 2-chloroacetophenon in10 ml of CH₃ CN was refluxed for 48 h. The reaction mixture was cooledto room temperature and stirred for one hour. The precipitate wasfiltered off to give 260 mg (67%) of3chloro-2-methyl-7-phenacylpyrrolo-[2,3-b]pyridinehydrochloride.

(¹ H-NMR, 500 MHz, DMSO-d ₆) 2.50(s,3H), 6.62(s,2H), 7.68(t,2H), 7.78(m,2H), 8.11(d, 2H), 8.62(d, 1H), 8.70(d, 1H).

Example 10

2,3-Dimethyl-7-(p-bromophenacyl)pyrrolo[2,3-b]pyridine, hydrobromide

This compound was prepared by reacting 2,3-dimethylpyrrolo[2,3-b]pyridine with p-bromophenacyl bromide following the procedure inexample 8.

Yield: 92%.

(¹ H-NMR, 300 MHz, DMSO-d₆) 2,29(s, 3H), 2,41(s, 3H), 6,47(s, 2H),7,63(dd, 1H), 7,92(m, 2H), 8,03(m, 2H), 8,43(d, 1H), 8,64(d, 1H),12,8(b, 1H)

Example 11

2,3-Dimethyl-7-(2-phenyl-2-hydroxyethyl)pyrrolo[2,3-b]pyridine.

A solution of 2,3-dimethyl-7-phenacylpyrrolo[2,3]pyridine (120 mg, 0.4mmol) in 3 ml MeOH was treated twice with 20 mg NaBH₄ ⁻ portions andallowed to react for 2h at room temperature. The solvent was evaporatedand the residue partitioned between 50 ml CH₂ Cl₂ and 25 ml 2.5% NaOH.The organic layer was separated, washed with 10 ml 2M HCl, dried overMgSO₄ and evaporated leaving 113 mg (94%) title compound as thehydrochloride.

(¹ H-NMR, 300 MHz, DMSO-d6). 2.26(s,3H), 2.48(s,3H), 4.81(dd, 1H),4.97(dd, 1H), 5.15(dd, 1H), 5.91(dd, 1H), 7.37(m, 3H), 7.53(t,1H),7.61(d,2H), 8.51(t,2H), 13.4(b, 1H).

Example 12

3-Chloro-2-methyl-7-(2-phenyl-2-hydroxyethyl)pyrrolo[2,3-b]pyridine

To a solution of 120 mg (0,37 mmol) of3-chloro-2-metyl-7-phenacylpyrrolo[2,3-b]pyridine hydrochlorid in 2 mlmethanol was added 30 mg (0,79mmol) of sodium borohydride. The mixturewas stirred for 20 h at room temperature. The solvent was evaporated andthe residue was partitioned between 2 ml of 0,2M hydrochloric acid and 2ml of ethyl acetate. The aqueos layer was basified by addition of 2Msodium hydroxide and extracted twice with 2 ml of methylene chloride.The combined organic phase was dried over sodium sulfate and the solventwas evaporated. The residue was treated with acetonitrile and theprecipitate was filtered off to give 20 mg (19%)3-chloro-2-methyl-7-(2-phenyl-2-hydroxyethyl)pyrrolo-[2,3-b]pyridine.

(¹ H-NMR, 500 MHz, CDCl₃) 2.55(s,3H), 4.76(dd, 1H), 4.91(dd, 1H),5.32(dd, 1H), 6.73(dd, 1H), 7.20(d,1H), 7.25(m, 1H), 7.28(m,4H), 7.88(d,1H).

Example 13

2,3-Dimethyl-7-(2-(p-cyanophenyl)-2-hydroxyethyl)pyrrolo[2,3-b]pyridine.

The title compound was prepared on a 0.4 mmol scale mainly according toexample 11 above yielding 68 mg (61%) pure title compound as a yellowsolid.

(¹ H-NMR, 300 MHz, CDCl₃). 2.27(s,3H), 2.51(s,3H), 4.73(dd,1H), 4.91(dd,1H), 5.36(dd, 1H), 6.65(t,1H), 7.03(d, 1H), 7.40(d,2H), 7.56(d,2H),7.78(d, 1H).

Example 14

2-Methyl-7-phenacyl-pyrrolo[2,3-b]pyridine hydrochloride

2-Methyl-pyrrolo[2,3-b]pyridine (0.5 g, 3.78 mmol), phenacyl chloride(0.62 g, 4.0 mmol ) and acetonitrile (10 ml) were refluxed for 12 h. Thesolid was filtered off and washed with cold carbon tetrachlorid (2 ml).The crude product was recrystallized from chloroform/ether, 1:1, to give0.95 g (88%) title compound.

(¹ H NMR, 300 MHz, DMSO-d₆); 1.25(s,3H), 6.65(s,2H), 6.70(s,1H), 7.65(m,3H), 7.80(t,1H), 8.10(d,2H), 8.50(d, 1H), 8.65 (d, 1H).

Example 15

2,3-Dimethyl -7(2-trifluoromethylphenacyl)-pyrrolo[2,3-b]pyridinehydrobromide

The title compound was made according to the general method from Example14. 2,3 -dimethyl-pyrrolo[2,3-b]pyridine (438 mg, 3 mmol),2-trifluoromethylphenacyl bromide (798 mg, 3 mmol ) in acetonitrile (5ml). Yield 0.44 g (36% ).

(¹ H-NMR, 300 MHz, DMSO-d₆), 2.45(s,3H), 2.50(s,3H),6.55(s,2H),7.65(t,1H), 7.95(t,1H), 8.05(m,2H), 8.40(d,2H), 8.65 (d, 1H).

Example 16

3-Bromo-2-methyl-7-phenacyl-pyrrolo[2,3-b]pyridine hydrobromide.

The title compound was made according to the general method from Example14. 3-bromo-2-methyl-pyrrolo[2,3-b]pyridine (250 mg, 1.19 mmol) phenacylbromide (200 mg, 1.3 mmol) in acetonitrile (50 ml). Yield 146 mg (37%).

(¹ H-NMR, 300 MHz, DMSO-d₆), 2.5(s,3H), 6.7 (s, 2H), 7.65(t, 1H),7.75(m,3H), 8.1(d,2H) , 8.6(m,2H).

Example 17

2-Chloro-3-methyl-7-phenacylpyrrolo-[2,3-b]pyridine. Hydrochloride.

A solution of 1.2 g (7.2mmol) 2 -chloro-3 -methylpyrrolo [2,3 b]pyridineand 1.3 g (8.7 mmol) phenacyl chloride in 50 ml acetonitrile wasrefluxed for 48 h. The solvent was allowed to cool and the precipitatedproduct was filtered off and dried, affording 1,5 g (65%) pure titlecompound.

(¹ H-NMR, 300 MHz, CDCl₃) 2.35(s,3H), 7.0(s,2H), 7.4(dd, 1H),7.55(t,2H), 7.65(t,1H), 7.8(d, 1H) , 8.2-8.3(m,3H).

Example 18

2-Chloro-3-methyl-7-(2-phenyl-2-hydroxyethyl)pyrrolo[(2,3-b]pyridine

A solution of 0,8 g (2,5 mmol)2-chloro-3-methyl-7-phenacylpyrrolo[2,3-b]pyridine in 50 ml methanol wascooled to 0° C. It was then treated with NaBH₄ -portions until allstarting material had reacted. (The reaction was followed by TLC). Thesolvent was evaporated and the residue partitioned between methylenechloride and water. The organic layer was separated, dried over Na₂ SO₄and evaporated. The residue was treated with ether and isolated byfiltration to give 0,6 g (84%) of the title compound as white solid.

(¹ H-NMR, 300 MHz, CD₃ OD) 2.3(s,3H), 4.5(dd, 1H), 4.9(dd, 1H), 5.25(dd,1H), 6.95(t,1H), 7.25-7.4(m, 3H), 7.5(d,2H), 7.85(d, 1H), 8.0(d, 1H).

Example 19

3-Methoxy-2-methyl-7-phenacyl pyrrolo[2,3-b]pyridine. Hydrochloride.

A solution of 0,75 g (4,6 mmol) 3-methoxy-2-methylpyrrolo[2,3-b]pyridineand 0,75 g (4,8 mmol) phenacyl chloride in 50 ml acetonitrile wasrefluxed for 14 h. Working up in the same manner as ex. 17 gave 0,5 g(34%) of the desired product.

(¹ H-NMR, 300 MHz, CDCl₃) 2.55(s,3H), 3.95(s,3H), 7.0(s,2H), 7.35 (t,1H), 7.5(t,2H), 7.6(t,1H), 7.9(d, 1H), 8.25(d,2H), 8.35 (d, 1H).

Example 20

2-Methoxymethyl-3-methyl-7-phenacyl pyrrolo[2,3-b]pyridine.Hydrochloride.

A solution of 0,13 g (0,74 mmol) 2-methoxymethyl-3-methylpyrrolo[2,3-b]pyridine and 0,16 g (1,1 mmol) phenacyl chloride in 20 mlacetonitrile was refluxed for 15 h. Working up in the same manner as ex.17 gave 0,05 g (20%) of the title compound.

(¹ H-NMR, 300 MHz, CDCl₃), 2.4(s,3H), 3.45(s,3H), 4.8(s,2H), 7.05(s,2H),7.4(dd, 1H), 7.55(t,2H), 7.65 (t, 1H), 7.85 (d, 1H), 8.25(d,2H), 8.35(d,1H).

Example 21

2-Chloro-3-methyl-7-(p-fluorophenacyl)pyrrolo[2,3-b]pyridinehydrochloride

A solution of 1,2 g (7,2 mmol) 2-chloro-3-methylpyrrolo[2,3-b]pyridineand 1,5 g (8,7 mmol) p-fluorophenacyl chloride in 50 ml acetonitrile wasrefluxed for 48 h. The mixture was allowed to cool and the precipitatedproduct filtered off. The solid was treated with ethyl acetate andfiltered off again affording 1,4 g (57%) of the desired product.

(¹ H-MNR, 300 MHz, CD₃ OD) 2.4(s,3H), 6.45(S,2H), 7.4(dd,2H), 7.65(dd,1H) , 8.25(dd, 2H), 8.45(cl, 1H), 8.7(d, 1H) .

Example 22

2-Chloro-3-methyl-7-(2-(p-fluorophenyl)-2-hydroxyethyl)pyrrolo[2,3-b]pyridine.

A solution of 1,0 g (2,8 mmol) of2-chloro-3-methyl-7-(p-fluorophenacyl)pyrrolo [2,3-b]pyridinehydrochloride in 50 ml methanol was treated with NaBH in the same manneras ex. 18 to give 0,85 g (99%) of the title compound as white solid.

(¹ H-NMR, 300 MHz, CD₃ OD) 2.3(s,3H), 4.5(dd,1H), 4.9(dd, 1H), 5.3(dd,1H), 6.95(t,1H), 7.1(t,2H), 7.45-7.55(m,2H), 7.8(d, 1H), 8.0(d, 1H).

Example 23

2-Chloro-3-cyanomethyl-7-phenacylpyrrolo[2,3-b]pyridine

A solution of 0,66 g (3,4 mmol)2-chloro-3-cyanomethyl-pyrrolo[2,3-b]pyridine, and 0,65 g (3,8 mmol)phenacyl bromide in 40 ml acetonitrile was refluxed for 20 h. Themixture was allowed to cool and the precipitated product was filtred offand recrystallized from acetonitrile. Chromatography on silica geleluting with ethyl acetate gave the desired product (0,094g, 9%).

(¹ H-NMR, 300 MHz, CDCl₃) 3.9(s,2H), 6.15(s,2H), 7.05(t,1H),7.5-7.65(m,3H), 7.7(t,1H), 8.1(d,2H), 8.25(d, 1H).

Example 24

2,3-Dimethyl-7-(o-methylthiophenacyl)pyrrolo[2,3-b]pyridinehydrobromide.

A solution of 0,2 g (1,4 mmol) 2,3-dimethylpyrrolo[2,3-b]pyridine and0,34 g (1,4 mmol) o-methylthiophenacyl bromide was stirred at roomtemperature for 4 h. The precipitated product was filtred off and driedaffording 0,11 g (20%) of the title compound.

(¹ H-NMR, 300 MHz, CDCl₃) 2.25(s,3H), 2.45(s,3H), 2.6(s,3H), 6.9(s,2H),7.35-7.45(m,3H), 7.6(t,1H), 7.75(d, 1H), 8.25(d, 1H), 8.65(d,1H).

Example 25

3-Hydroxy-2-methyl-7-phenacylpyrrolo[2,3-b]pyridine.

To a solution of 0,05 g (0,16 mmol) 3-methoxy-2-methyl-7-phenacylpyrrolo[2,3-b]pyridine in 10 ml methylene chloride was added 0,5 ml (0,2mmol) bortribromide in methylene chloride (1M) at RT. The reaction wasfollowed by T.L.C. The mixture was stirred 20 h. and was evaporated. Theproduct was solved in 2 ml methylene chloride/methanol 10/1 and a smallamount of water and chromatography of this mixture on silica gel elutingwith methylene chloride/methanol 10/1 gave the product as an oil. Theoil was treated with ether to give the title product as yellow solid.

(¹ H-NMR, 300 MHz, DMSO-d₆), 2.35(s,3H), 6.45(s,2H), 7.55(bs,1H),7.7(t,2H), 7.8(t,1H), 8.15(d,2H), 8.4(d, 1H), 8.6(d, 1H).

Example 26

2,3-Dimethyl-5-trifluoromethyl-7-phenacylpyrrolo[2,3-b]pyridine

A solution of 0,1 g (0,47 mmol)2,3-dimethyl-5-trifluoromethyl-pyrrolo[2,3-b]pyridine and 0,13g (0,84mmol) 2-chloroacetophenone in 5 ml acetronitrile was refluxed for 48 h.The solvent was evaporated. Chromatography on silica gel eluting withmethylene chloride and methanol (100:5) gave the desired product. (0,023g 15%).

(¹ H-NMR, 300 MHz, CDCl₃) 2.3(s,3H), 2.45(s,3H), 6.15 (s, 2H),7.55(t,2H), 7.65(t,1H), 7.75(s,1H), 7.95(s,1H), 8.05(d, 2H).

Example 27

2,3Dimethyl-7-(p-cyanophenacyl)pyrrolo[2,3-b]pyridine.

A solution of 2,3-dimethylpyrrolo[2,3-b]pyridine (146 mg, 1 mmol) andp-cyanophenacyl bromide (248 mg, 1.1 mmol) in 3 ml CH₃ CN was refluxedfor 1.5 h. The mixture was allowed to cool and the precipitated productfiltered off and washed with a small volume of ice cold CCl₄ affording313 mg (85%) pure title compound as the hydrobromide salt.

(¹ H-NMR, 300 MHz, CDCl₃) 2.30(s,3H), 2.50(s,3H), 7.10(s,2H),7.40(dd,1H), 7.68(d,2H), 8.00(d, 1H), 8.29(d,1H), 8.39(d,2H),13.6(b,1H).

Example 28

2,3-Dimethyl-7-(p-fluorophenacyl)pyrrolo[2,3.-b ]pyridine.

The title compound was prepared on a 1 mmol scale from2,3-dimethylpyrrolo[2,3-b]pyridine and p-fluorophenacyl bromidefollowing the procedure in example 27 above yielding 260 mg (64%) pureproduct as the hydrobromide.

¹ H-NMR, 300 MHz, CDCl₃), 2.28(s,3H) 2.56(s,3H), 6.99(s,2H), 7.18(m,2H),7.38(dd, 1H), 7.83 (d, 1H), 8.24 (d, 1H), 8.35(m,2H), 13.8(b,1H).

Example 29

2,3 -Dimethyl-7-(p-metoxyphenacyl)pyrrolo[2,3-b]pyridine.

The title compound was prepared from 2,3-dimethylpyrrolo [2,3-b]pyridine(120 mg, 0.82 mmol) and p-methoxyphenacyl bromide (207 mg, 0.90 mmol)following the procedure in example 27 above furnishing 223 mg (73%) purehydrobromide as a light yellow solid.

(¹ H-NMR, 300 MHz, CDCl₃) 2.27(s,3H), 2.58(s,3H), 3.88(s,3H),6.91(s,2H), 7.00(m, 2H), 7.37 (dd, 1H), 7.81(d, 1H), 8.22(d, 1H),8.28(m,2H).

Example 30

2,3-Dimethyl-7- (m-methoxyphenacyl)pyrrolo[2,3-b]pyridine.

The title compound was prepared on a 0.9 mmol scale fr2,3-dimethylpyrrolo[2,3-b]pyridine and m-methoxyphenacyl bromide in thesame manner as described in example 27 giving 228 mg (70%) pure productas the hydrobromide.

(¹ H-NMR, 300 MHz, CDCl₃ ). 2.27(s,3H), 2.57(s,3H), 3.91(s,3H),6.97(s,2H), 7.18(dd, 1H), 7.37 (dd, 1H), 7.43 (t, 1H), 7.75 (bt, 1H),7.79 (d, 1H), 7.89(d, 1H), 8.22 (d, 1H).

Example 31

2,3-Dimethyl-7-(o-methoxyphenacyl)pyrrolo[2,3-b]pyridine.

The title compound was prepared on a 1 mmol scale from2,3-dimethylpyrrolo[2,3-b]pyridine and o-methoxyphenacyl bromide in thesame manner as described in example 27 yielding 244 mg (71%) purehydrobromide as a light yellow solid.

(¹ H-NMR, 300 MHz, CDCl₃). 2.26(s,3H), 2.60(s,3H), 4.20(s,3H),6.71(s,2H), 7.04(m, 1H), 7.11(d, 1H), 7.35 (dd, 1H), 7.59 (m, 1H) , 7.69(d, 1H), 7.95 (dd, 1H), 8.20 (d, 1H).

Example 32

2,3-Dimethyl-7-(2,4-difluorophenacyl)pyrrolo[2,3-b]pyridine.

The title compound was prepared on a 1 mmol scale from2,3-dimethylpyrrolo[2,3 -b]pyridine and o,p-difluorophenacyl bromidefollowing the procedure described in example 27 giving 194 mg (56%) purehydrochloride as a yellow solid.

(¹ H-NMR, 300 MHz, CDCl₃) 2.27(s,3H), 2.53(s,3H), 6.76(d,2H), 6.96 (moverlapping signals, 2H), 7.34(dd, 1H), 7.80(d, 1H), 8.15(m, 1H),8.22(d, 1H), 14.9(b, 1H).

Example 33

5-Chloro-3-cyanomethyl-2-methyl-7-phenacylpyrrolo[2,3-b]pyridine

A mixture of 5-chloro-3-cyanomethyl-2-methyl-pyrrolo[2,3-b]pyridine (147mg, 0.7 mmol) and phenacylbromide (142 g, 7 mmol) in 12 ml CH₃ CN wasrefluxed for 22h. The reaction mixture was cooled and precipitated titlecompound was collected and washed with small portions of ice colddiethyl ether. Treatment of the filtrate with diethyl ether afforded asecond and third lot of pure title compound. Total yield 257 mg (91%)calculated as the hydrobromide.

(¹ H-NMR, 300 MHz, DMSO-d₆). 2.53(s,3H), 4.24(s,2H), 6.50(s,2H),7.70(t,2H), 7.83(t,1H), 8.10(d,2H), 8.90(d, 1H), 9.042 (s,1H ).

Example 34

2,3 -Dimethyl-7-[2-phenyl-2-methoxyethyl)-pyrrolo[2,3-b]pyridine

A solution of2,3-dimethyl-7-(2-phenyl-2-hydroxyethyl)pyrrolo[2,3-b]pyridine (as thebase) (266 mg, 1.0 mmol) in 25 ml dry THF was deaerated and treated with55% NaH dispersion in oil (48 mg, 1.1 mmol) for 30 min. Methyl iodide(62 μl, 1.0 mmol) was added and allowed to react for 50 min. The solventwas evaporated and the residue partitioned between 100 ml CH₂ Cl₂ and 20ml 5% NaOH. The organic layer was dried over MgSO₄ and evaporated. Theresidue was chromatographed (silica, CH₂ Cl₂ saturated with NH₃). Purefractions were pooled and evaporated leaving a gum which partlycrystallized. Trituation with diethyl ether furnished 207 mg (65%) puretitle compound.

(¹ H-NMR, 300 MHz,CDCl₃). 2.29(s,3H), 2.54(s,3H), 3.14(s,3H), 4.41(dd,1H), 4.86(dd, 1H), 4.99(dd, 1H), 6.64(t,1H), 7.38 (overlapping signals,6H), 7.75(d, 1H).

Example 35

2,3-Dimethyl-7-(o-nitrophenacyl)pyrrolo[2,3-b]pyridine.

The title compound was prepared on a 5 mmol scale from2,3-dimethylpyrrolo[2,3-b]pyridine and o-nitrophenacyl bromide in thesame manner as described in example 27 yielding 1.3 g (66%) purehydrobromide as a yellow solid. Reprocessing of the motherliquor gaveadditional material.

(¹ H-NMR, 300 MHz, DMSO-d₆). 2.30(s,3H), 2.47(s,3H), 6.38(s,2H),7.68(dd, 1H), 7.97(dt,1H), 8.08(t,1H), 8.21(dt,2H), 8.37(d, 1H), 8.67(d,1H), 12.9(b,1H).

Example 36

2,3-Dimethyl-7-(o-aminophenacyl)pyrrolo[2,3-b]pyridine.

2,3-Dimethyl-7-(o-nitrophenacyl)pyrrolo[2,3-b]pyridine (1.02 g, 2.6mmol) was dissolved in 39 ml abs. EtOH and treated with SnCl₂.2H₂ O(4.75 g, 21 mmol) and 13 ml conc HCl at 80° C. for 3h. The reactionmixture was allowed to cool and then partitioned between 500 ml 2M HCland 250 ml CH₂ Cl₂. The organic layer was extracted with additional 150+50 ml 2M HCl. The aqueous layers were combined and washed with 400 mldiethyl ether. The pH was adjusted to 12 and the basified productextracted with 800+400+200 ml CH₂ Cl₂. The latter organic layers werecombined, dried over MgSO₄, and evaporated leaving 340 mg (46%) pureamine as an intense yellow solid.

(¹ H-NMR, 300 MHz, CDCl₃). 2.28(s,3H), 2.47(s,3H), 6.09(s,2H),6.21(b,2H), 6.71(m,2H), 6.81(t,1H), 7.33(m,2H), 7.82(d,1H), 7.88(d, 1H).

Example 37

2,3-Dimethyl-7-[p-methylphenacyl)pyrrolo[2,3-b]pyridine.

A solution of 2,3-dimethylpyrrolo[2,3-b]pyridine (0.16 g, 1.1 mmol) andp-methylphenacyl bromide (0.26 g, 1.2 mmol) in 4.5 ml CH₃ CN was warmedto reflux which was enough to initiate crystallisation of the product asa light yellow solid. The precipitate was isolated as described inexample 27 furnishing 0.29 g (74%) pure hydrobromide.

(¹ H-NMR, 300 MHz, CDCl₃). 2.27(s,3H), 2.41(s,3H), 2.57(s,3H),6.94(s,2H), 7.32(d,2H), 7.37(dd, 1H), 7.80(d, 1H), 8.17(d,2H), 8.23(d,1H), 13.8(b, 1H).

Examples 38 and 39

(R andS)-2,3-dimethyl-7-(2-phenyl-2-hydroxyethyl)pyrrolo-[2,3-b]pyridinehydrochloride.

R(-)-2-methoxy-2-phenylacetic acid was dissolved in 3 ml SOCl₂ at 0° C.and allowed to react for 4h at room temperature. The excess SOCl₂ wasevaporated and the residue treated with a solution of a racemic mixtureof 2,3 -dimethyl-7-(2-phenyl-2-hydroxyethyl)pyrrolo[2,3 -b]pyridineprepared according to Example 11 (302 mg, 1.0 mmol) and Et₃ N (279 μl,2.0 mmol) in 20 ml CH₂ Cl₂. After reacting for 16h at room temperaturethe mixture was paritioned between 150 ml CH₂ Cl₂ and 50 ml 2M HCl. Theorganic layer was collected washed with 50 ml 5% Na₂ CO₃, dried overMgSO₄, and evaporated. Diastereomers 1 and 2 were separated bychromatography (silica, CH₂ Cl₂ saturated with NH₃ /diethyl ether;1/1).Diastereomer 2 was further purified by chromatography (silica, CH₂ Cl₂saturated with NH₃). Yields, 149 mg (36%) and 90 mg (22%) of isomers 1and 2, respectively. Each isomer (149 mg, 0.36 mmol 1 and 89 mg, 0.21mmol 2) was dissolved in a few ml of MeOH and LiOH (a 5-fold molarexcess) dissolved in a few ml H2O was added and allowed to react for 1 hat room temperature. The solvent was evaporated and each residuepartitioned between 100 ml CH₂ Cl₂ and 50 ml 5% Na₂ CO₃. Each organiclayer was washed once with 50 ml 2M HCl, dried over MgSO₄, andevaporated leaving 100 mg (92%) enantiomer 1 and 52 mg (82%) enatiomer2.

(¹ H-NMR, 300 MHz, DMSO-d₆). Cf. Example 11.

Example 40

2,3-Dimethyl-7-(o-hydroxyphenacyl)pyrrolo[2,3-b]pyridine.

A solution of 2,3-dimethyl-7-(o-methoxyphenacyl) pyrrolo[2,3-b]pyridine(75 mg, 0.2 mmol) in 20 ml CH₂ Cl₂ was cooled to 0° C. and treated with1M BBr₃ in CH₂ Cl₂ (200 μl, 0.2 mmol). After reacting for an additionalhour the reaction mixture was poured into a stirred solution of 5%NaHCO₃. The aqueous layer was attracted with 50+10 ml CH₂ Cl₂ and thecombined organic layers washed With 50 ml 2M HCl (reextraction tricewith 10 ml CH₂ Cl₂). The combined organic layers were dried over MgSO₄and evaporated. The residue was chromatographed (silica, CH₂ Cl₂ /MeOH;9/1) affording 35 mg (62%) pure title compound.

(¹ H-NMR 500 MHz, CDCl₃) 2 27(s,2H), 2.50(s,3H) 6.40(b,2H), 6.93(b,1H),6.98(d,1H), 7.14(t,1H), 7.40(b,1H), 7.6(d, 1H), 7.85(b,1H), 8.07(d,1H).

Example 41

2,3-Dimethyl-6-methylthio-7-phenethylpyrrolo[2,3-b]pyridine.

A refluxing solution of 2,3-dimethyl-6-mehylthiopyrrolo[2,3-b]pyridine(100 mg, 0.5 mmol) in 5 ml CH₃ CN was treated with five portions ofphenethyl bromide (85 μl, 1.2 mmol), one each 24 h. The solvent wasevporated and the residue chromatographed (silica, CH₂ Cl₂ saturatedwith NH₃ /diethyl ether/petroleum ether; 5/2/3) affording 20 mg (13%)pure title compound.

(¹ H-NMR 500 MHz CDCl₃) 2.27(s,3H), 2.52(s,3H), 2.53(s,3H), 3.25(m, 2H),5.10(m, 2H), 6.75(d,1H), 7.25(m, 1H), 7.31 overlapping signals, 4H),7.68(d,1H).

Example 42

2,3-Dimethyl-7-phenethyl-6-phenethylthiopyrrolo[2,3-b]pyridinehydrochloride

A refluxing solution of 2,3-dimethyl-6-methylthio-pyrrolo[2,3-b]pyridine (391 mg, 2.0 mmol) in 9 ml CH₃ CN was treated with fiveportions of phenethyl bromide (553 μl, 4.0 mmol), one each 24 h. Thesolvent was evaporated and the residue chromatographed (silica, CH₂ Cl₂saturated with NH₃ /diethyl ether/petroleum ether; 5/2/3). Purefractions were pooled, diluted to the double volume with CH₂ Cl₂ andwashed with 50 ml 2M HCl. The organic layer was dried over MgSO₄ andevaporated leaving 221 mg (26%) pure product.

(¹ H-NMR, 500 MHz, CDCl₃), 2.29(s,3H), 2.55(s,3H), 2.90(t,2H),3.16(t,2H), 3.24(m,2H), 5.14(m, 2H), 6.92(d, 1H), 7.13(d,2H),7.23(overlapping signals, 4H), 7.29 (overlapping signals, 4H), 7.68(d,1H).

Example 43

2,3-Dimethyl-6-methylthio-7-phenacylpyrrolo[2,3-b]pyridine.

A mixture of 2,3-dimethyl-6-methylthiopyrrolo[2,3-b]pyridine (100 mg,0.5 mmol) and phenacyl chloride (804 mg, 5 mmol) in 3 ml CH₃ CN wasrefluxed for 72 h. The solvent was evaporated and the residuechromatographed (silica, CH₂ Cl₂ /MeOH;59/5). Pure fractions werepooled, evaporated, and taken up in 100 ml CH₂ Cl₂. The organic layerwas washed with 25 ml 2M HCl, dried over MgSO₄, and evaporated leaving64 mg (35%) pure product as the hydrochloride.

(¹ H-NMR of the free base, 300 MHz, CDCl₃). 2.25(s,3H), 2.45(s,3H),2.53(s,3H), 6.62(b,2H), 7.05(d, 1H), 7.55(m,2H), 7.66(m,1H), 7.85(d,1H),8.12(m,2H).

Example 44

2,3-Dimethyl-5-methylthio-7-phenacylpyrrolo[2,3-b]pyridine.

The title compound was prepared on a 0.6 mmol scale from2,3-dimethyl-5-methylthiopyrrolo[2,3-b]pyridine (prepared according tothe procedure described for2,3-dimethyl-6-methylthio-pyrrolo[2,3-b]pyridine) and phenacyl chlorideas described in Example 43 yielding 140 mg (63%) pure title compound asthe hydrochloride.

(¹ H-NMR, 500 MHz, CDCl₃). 2.26(s,3H), 2.57(s,3H), 2.60(s,3H),6.95(b,2H), 7.60(m,2H), 7.69(m,2H), 8.22(s,1H), 8.30(m,2H).

Example 45

2,3-Dimethyl-5-methylsulfinyl-7-phenacylpyrrolo[2,3 -b]pyridine.

A solution of 2,3-dimethyl-5-methylthio-7-phenacylpyrrolo[2,3-b]pyridine(35 mg, 0.1 mmol) in 20 ml CH₂ Cl₂ was cooled to -20° C. an treated with71% m-CPBA (27 mg, 0.1 mmol) for 30 min. The volume was adjusted 50 mlwith CH₂ Cl₂ and the organic layer washed twice with 50 ml 5% Na₂ CO₃and once with 2M HCl (reextraction trice with 25 ml CH₂ Cl₂). Theorganic layer was dried over MgSO₄ and evaporated leaving 15 mg (41%)pure title compound.

(¹ H-NMR of the hydrochloride, 300 MHz, CDCl₃). 2.31(s,3H), 2.59(s,3H),2.95(s,3H), 7.05(s,2H), 7.54(t,2H), 7.66(t,1H), 8.16(s,1H), 8.25(d,2H),8.36(s,1H).

Example 46

2,3-Dimethyl-7-(o-carboxyphenethyl)pyrrolo[2,3-b]pyridine.

A solution of 2,3-dimethylpyrrolo[2,3-b]pyridine (554 mg, 3.8 mmol) ando-bromophenethyl bromide (1000 mg, 3.8 mmol) in 11 ml CH₃ CN wasrefluxed for 16 h. The solvent was evaporated and the residuechromatographed (silica, CH₂ Cl₂ /MeOH; 9/1) to give 546 mg enrichedproduct. Pure 2,3-dimethyl-7-(o-bromophenethyl) pyrrolo[2,3-b]pyridinewas obtained by a second chromatography (silica, CH₂ Cl₂ saturated withNH3/petroleum ether; 7/3). A deaerated solution of 2,3-dimethyl-7-(o-bromophenethyl) pyrrolo[2,3-b]pyridine (249 mg, 0.76 mmol) in 25 mldry THF was cooled to -78° C. and treated with 1.6M n-BuLi in hexane(576 μl, 0.91 mmol). After 3 min a vigurous stream of CO₂ (g) wasbubbled through the solution. The solution was allowed to warm to roomtemperature and 1.5 ml H₂ O was added. The solvent was evaporated andthe residue chromatographed (reversed phase silica, MeOH/H₂ O; 6/4)yielding 51 mg (23%) pure amino acid.

(¹ H-NMR of the hydrochloride, 300 MHz, CDCl₃). 2.22(s,3H), 2.56(s,3H),3.55(t,2H), 5.07(t,2H), 6.86(d, 1H), 7.04(m, 1H), 7.19(m, 1H), 7.24(m,1H), 7.83(dd, 1H), 7.91(d, 1H), 8.09(d,1H).

Example 47

5-Bromo-2,3-dimethyl-7-phenacyl pyrrolo[2,3-b]pyridine.

A solution of 5-bromo-2,3 -dimethyl-pyrrolo [2,3 -b]pyridine (preparedin a similar manner as 6-bromo-2,3-dimethyl-pyrrolo[2,3-b]pyridine (200mg, 0.9 mmol) and phenacyl bromide (200 mg, 1.3 mmol) in 15 ml CH₃ CNwas refluxed for 16 h. The mixture was allowed to cool and theprecipitated product filtered off and washed with a small volume ofdiethyl ether affording 243 mg (72%) pure title compound as thehydrochloride.

(¹ H-NMR, 500 MHz, DMSO-d₆). 2.28(s,3H), 2.43(s,3H), 6.58(s,2H),7.68(t,2H), 7.81(t,1H), 8.09(d,2H), 8.84(s,1H), 8.95(s,1H).

Example 48

5-Cyano-2,3-dimethyl-7-phenacyl pyrrolo[2,3-b]pyridine.

A mixture of 5-cyano-2,3-dimethyl-pyrrolo [2,3-b]pyridine (77 mg, 0.5mmol ) and phenacyl chloride (650 mg, 4.2 mmol ) in 12 ml CH₃ CN wasrefluxed for 62 h. The mixture was basified with a saturated Na₂ CO₃solution and extracted with CH₂ Cl₂. The organic layer was dried overMgSO₄ and evaporated. The residue was chromatographed (silica, CH₂ Cl₂/diethyl ether;7/3) yielding 34 mg (26%) pure title compound.

(DI-MS, E1 at 70 eV) m/z 289 (25) , 260 (15), 171 (38), 170 (50), 146(32), 105(100).

(¹ H-NMR, 300 MHz, CDCl₃) 2.26(s,3H), 2.43(s,3H), 6.09(s,2H),7.54(t,2H), 7.68(t,1H), 7.75(d, 1H), 7.89(d, 1H), 8.06(overlappingsignals, 2H).

Example 49

Preparation of 3-cyanomethyl-2-methyl-7-phenacyl-pyrrolo[2,3-b]pyridinehydrochloride.

A solution of 1.0 g (5.8 mmol) of 3-cyano-methyl-2-methylpyrrolo[2,3-b]pyridine and 1.08 g (7.0 mmol) of phenacyl chloride in 50ml acetonitrile was refluxed for 14 h. Working up in the same manner asdescribed in example 17 gave 0,5 g 58% of the desired title compound.

(¹ H-NMR, 300 MHz, DMSO-d₆), 2.50(s,3H), 4.25(s,2H), 6.62(s,2H),7.6-7.83(m, 4H), 8.10(d,2H), 8.56(d, 1H), 8.79(d,1H).

Example 50

Preparation of 3-(1-pyrazolo)methyl-2-methyl-7-phenacyl pyrrolo[2,3-b]pyridine.

A solution of 30 mg (0.14 mmol) of 3-(1-pyrazolo)methyl-2-methylpyrrolo[2,3-b]pyridine and 32 mg (0.21 mmol) of phenacyl chloride in 1ml acetonitrile was refluxed for 10 h. The solvent was evaporated andthe crude product was treated with acetonitrile and the product wasisolated by filtration. The product was partitioned between methylenechloride and a saturated sodium bicarbonate solution. The organic layerwas dried over sodium sulfate and the solvent was evaporated to give 18mg (39%) of the title compound.

(¹ H-NMR, 300 MHz, CD₃ OD), xHCl, 2.60(s,3H), 5.60(s,2H), 6.32(t,1H),6.42(b,2H), 7.5-7.8 (m,6H), 8.15(m,2H), 8.33(d,1H), 8.49 (d,1H).

Example 51

Preparation of 3-cyanomethyl-2-methyl-7-(4-fluorophenacyl)pyrrolo[2,3-b]pyridine hydrochloride.

A solution of 7 5 mg (0.44 mmol) of 3-cyanomethyl-2-methyl-pyrrolo [2,3-b]pyridine and 99 mg(0.57 mmol) of 4-fluorophenacyl chloride in 1 mlacetonitrile was refluxed for 48 h. The solvent was evaporated and theresidue was treated with 0.4 ml acetonitrile. After filtration the solidwas treated with 0,3 ml methanol and 0,4 ml acetonitrile to give 75 mg(55% ) of the title compound.

(¹ H-NMR, 500 MHz, DMSO-d₆), 2.50(s,3H), 4.25(s,2H), 6.62(s,2H), 7.53(m,1H), 7.75(m, 1H), 8.20(dd,2H), 8.55(d,1H), 8.80(d, 1H).

Example 52

Preparation of2,3-dimethyl-7(2-(2-acetaminophenyl)-ethyl)pyrrolo[2,3-b]pyridinehydrobromide.

A solution of 73 mg (0,5 mmol) 2,3 dimethylpyrrolo[2,3-b]pyridine and122 mg (0,5 mmol) of (2-bromoethyl)acetanilide in 2 ml acetonitrile wasrefluxed for 10 h. The solvent was evaporated and the crude product wastreated with 5 ml petroleum ether:ether 1:1 and the insoluble fractionwas treated with ether. The etheral layer was separated from the oilyresidue, which crystallized from acetronitrile and gave 15 mg (7,7%) ofthe title compound.

(¹ H-NMR, 300 MHz, CDCl₃), 2.20(s,3H), 2.38(s,3H), 2.42(s,3H),3.38(t,2H), 5.08(t,2H), 6.48(m, 1H), 6.73(m, 1H), 7.08(m, 1H), 7.23-7.35(m,2H) , 8.09(d,1H) , 8.55(m, 1H), 10.1(s,1H).

Example 53

Preparation of 2,3-dimethyl-7(2.6-difluorophenacyl)pyrrolo [2,3 -b]pyridine hydrobromide.

A solution of 100 mg (0.68 mmol) 2,3-dimethylpyrrolo[2,3-b]pyridine and193 mg (0.82 mmol) 2,6-difluorophenacyl bromide in 2 ml acetonitrilewere refluxed for 3 h. Working up in the same manner as described inexample 17 gave 145 mg (54% ) of the desired product.

(¹ H-NMR, 300 MHz, CDCl₃) 2.28(s,3H), 2.62(s,3H), 6.72(s,2H),7.07(m,2H), 7.38 (m,1H), 7.58(m, 1H), 7.73(d,1H), 8.24(d, 1H).

Example 54

Preparation of 3-thiocyano-2-methyl-7-phenacylpyrrolo[2,3-b]pyridinehydrochloride

A solution of 100 mg (0.53 mmol) of 3-thiocyano-2-methyl pyrrolo[2,3-b]pyridine and 122 mg (0.79 mmol) of phenacyl chloride in 3 mlacetonitrile: dimethylformamide 2:1 was warmed at 70° C. for 36 h. Thereaction mixture was cooled to room temperature and the acetonitrile wasevaporated. To the residue was added 10 ml diethyl ether. Theprecipitated product was filtered off and washed with acetonitrilegiving 37 mg (23%) of the title compound.

(¹ H-NMR, 300 MHz, DMSO-d₆). 2.65(s,3H), 6.66(s,2H), 7.7(m,2H), 7.79-7.9(m,2H), 8.11(d,2H), 8.68(d,1H), 8.85(d,1H).

Example 55

2-(p-bromophenyl)-3-methyl-7-phenacyl pyrrolo[2,3-b]pyridine

The title compound was prepared from2-(p-bromophenyl)-3-methyl-pyrrolo-[2,3-b]pyridine and phenacylbromideon a 1.7 mmol scale according to the procedure described in example 8yielding 620 mg (74%).

(¹ H-NMR, 500 MHz, CDCl₃) 2.55 (s,3H), 7.35 (s, 2H), 7.50 (t, 1H), 7.60(t, 2H), 7.65 (d, 2H), 7.70 (t, 1H), 7.85 (m, 3H), 8.35 (d, 2H), 8.45(d, 1H).

Example 56

Methyl-p[3-methyl-7-phenacyl pyrrolo[2,3-b]-pyridine-2-yl]benzoate.

The title compound was prepared frommethyl-[p-(-3-methylpyrrolo[2,3-b]-pyridine)-2]yl benzoate andphenacylbromide on a 0.4 mmol scale according to the procedure describedin example 8 yielding 70 mg (46%).

(¹ H-NMR, 300 MHz, CDCl₃). 2.55 (s, 3H), 3.90 (s, 3H), 6.15 (s, 2H),6.90 (t, 1H), 7.55 (m, 3H), 7.65 (m, 1H), 8.0 (m, 5H), 8.15 (m, 2H).

Example 57

Isopropyl-[p(3-methyl-7-phenacyl-pyrrolo[2,3-b]pyridine)-2]yl benzoate

The title compound was prepared fromisopropyl-[p-(3-methyl-pyrrolo[2,3-b]-pyridine) -2]yl benzoate andphenacylbromide on a 0.2 mmol scale according to the procedure describedin example 8 yielding 25 mg (30%).

(¹ H-NMR, 300 MHz, CDCl₃). 1.35 (s, 3H), 1.40 (s, 3H), 2.55 (s, 3H),5.25 (m, 1H), 6.15 (s, 2H), 6.85 (t, 1H), 7.55 (m, 3H), 7.65 (t, 1H),8.05 (m, 5H), 8.15 (d, 2H).

Example 58

3-Methyl-2-phenyl-7-phenacyl pyrrolo[2,3-b]pyridine

The title compound was prepared from3-methyl-2-phenylpyrrolo[2,3-b]pyridine and phenacylbromide on a 4 mmolscale according to the procedure described in example 8 yielding 1.58 g(97%).

(¹ H-NMR, 500 MHz, CDCl₃). 2.24 (s, 3H), 7.39-7.56 (several overlappingsignals, 8H), 7.65 (t, 1H), 7.87 (d, 1H), 7.93 (overlapping d, 2H), 8.33(overlapping d, 2H), 8.39 (d, 1H), 13.6 (b, 1H).

Example 59

3-Methyl-2-(p-methylphenyl)-7-phenacylpyrrolo[2,3-b]pyridine

The title compound was prepared from3-methyl-2-(p-methylphenyl)-pyrrolo[2,3-b]pyridine and phenacyl bromideon a 3 mmol scale according to the procedure described in example 8yielding 1.21 g (96%).

(¹ H-NMR, 500 MHz, CDCL₃). 2.37 (s, 3H), 2.52 (s, 3H), 7.29 (d, 2H),7.37 (s, 2H), 7.43 (dd, 1H), 7.53 (t, 2H), 7.63 (t, 1H), 7.81 (d, 2H),7.86 (d, 1H), 8.33 (overlapping signals, 3H), 13.5 (b, 1H).

Example 60

2-(p-Methoxyphenyl)-3-methyl-7-phenacylpyrrolo[2,3-b]pyridine

The title compound was prepared from2-(p-methoxyphenyl)-3-methyl-pyrrolo[2,3-b]pyridine and phenacylbromideon a 10 mmol scale according to the procedure described in example 8yielding 4.02 g (92% ).

(¹ H-NMR, 300 MHz, CDCl₃). 2.50 (s, 3H), 3.83 (s, 3H), 7.00 (d, 2H),7.36 (s, 2H), 7.42 (dd, 1H), 7.53 (t, 2H), 7.63 (t, 1H), 7.82 (d, 1H),7.91 (d, 2H), 8.33 (overlapping signals, 3H), 13.5 (b, 1H).

Example 61

2,3-dimetyl-7-(2-phenyl-2-methoxyiminoetyl)-pyrrolo[2,3-b]pyridine (Eand Z isomers)

A mixture of 2,3-dimethyl-7-phenacylpyrrolo[2,3-b]pyridine hydrochloride(301 mg, 1 mmol) and methoxylamine hydrochloride (460 mg, 5 mmol) in 3ml MeOH and 4.5 ml pyridine was allowed to react for 5 days at roomtemperature. The methanol was evaporated and the residue partitionedbetween 150 ml CH₂ Cl₂ and 50 ml 2M HCl. The organic layer wascollected, dried over MgSO₄, and evaporated, Chromatography (silica, CH₂Cl₂ /MeOH;92.5/7.5) afforded 179 mg and 74 mg of each isomer,respectively.

Each isomer was dissolved in 100 ml CH₂ Cl₂ and washed with 20 ml 2MHCl, dried over MgSO₄, and evaporated leaving 198 mg (60%) of isomer 1and 70 mg (21%) of isomer 2. No attempts to establish thestereochemistry was done at this stage.

(¹ H-NMR of isomer 1, 300 MHz, CDCl₃). 2.27 (s, 3H), 2.57 (s, 3H), 4.10(s, 3H), 6.02 (s, 2H), 6.71 (t, 1H), 7.27 (signals overlapping withresidual CHCl₃, 3H), 7.38 (d, 1H), 7.70 (m, 2H), 7.74 (d, 1H).

(¹ H-NMR of isomer 2, 300 MHz, CDCl₃). 2.22 (s, 3H), 2.60 (s, 3H), 3.86(s. 3H), 6.19 (s, 2H), 7.13 (t, 1H), 7.31 (m, signals overlapping withresidual CHCl₃, 3H), 7.77 (m, 2H), 7.85 (d, 1H), 7.98 (d, 1H).

Example 62

2-Chloro-3-cyanomethyl-7-(2-phenyl-2-hydroxyethyl)pyrrolo[2,3-b]pyridine

A solution of 2-chloro-3-cyanomethyl-7-phenacylpyrrolo(2,3-b]pyridine(15 mg 0.05 mmol) in 3 ml MeOH was treated with 10 mg NaBH₄ and allowedto react for 30 min at room temperature. The solvent was evaporated andthe residue partitioned between CH₂ Cl₂ and water. The organic layer wasseparated, dried over Na₂ SO₄ and evaporated. Chromatography on silicagel eluting with ether gave the desired product (7 mg 46%).

(¹ H-NMR, 300 MHz, CD₃ OD): 4.0 (s, 2H), 4.55 (dd, 1H), 4.95 (s, 2H),5.3 (dd, 1H), 7.05 (dd, 1H), 7.25-7.4 (m, 3H), 7.5 (d, 2H), 7.95 (d,1H), 8.2 (d, 1H)

Example 63

Preparation of3-(cyanomethyl)-5-fluoro-2-methyl-7-phenacylpyrrolo[2,3-b]pyridinehydrobromide

A mixture of 3- (cyanomethyl)-5-fluoro-2-methylpyrrolo [2,3-b]pyridine(0.28 g, 1.5 mmol) and phenacyl bromide 0.32 g, 1.6 mmol) inacetonitrile (5 ml) was refluxed under argon for 3 h, during which timethe initial solution was transformed into a suspension. Then thesuspension was cooled in an ice bath, filtered and washed with diethylether (2×2 ml). The crystalline product was purified byrecrystallization from hot acetonitrile to give 0.52 g (90% ) of thetitle compound.

MS m/z (relative intensity) 307 (14, M+), 306(8), 279(10), 278(20),105(100), 91(41), 77(97).

Example 64

Preparation of5-bromo-3-methyl-7-phenacyl-2-phenylpyrrolo[2,3-b]pyridine

5-Bromo-3-methyl-2-phenylpyrrolo[2,3-b]pyridine (0.34 g, 1.2 mmol) andphenacyl bromide (0.49 g, 2.4 mmol) in acetonitrile (20 ml) was refluxedover night to give a clear solution. The cooled solution was alkalizedwith sodium carbonate solution (10%) and extracted with methylenechloride. Drying over MgSO₄, filtration and evaporation of solvents gavea residue which was dissolved in the minimum amount of ethanol.Crystallization was driven to completeness by keeping crystals andmother liquor in the fridge for a few days. Recrystallization bydissolving in hot ethanol and cooling in the fridge over night gave 0.35g (73%) of yellow crystals.

(free base, ¹ H-NMR, 300 MHz, CDCl₃) 2.50 (s, 3H), 6.12 (s, 2H), 7.29(dr, 1H, J₁ 7.5 Hz, J₂ 1Hz), 7.40 (t, 2H, J7 Hz), 7.52-7.60 (m, 3H),7.65-7.70 (m, 1H), 7.86-7.89 (m, 2H), 8.01 (d, 1H, J 2 Hz), 8.12 (d, 2H,J 7 Hz).

Example 65

Preparation of 3-cyanomethyl)-7-phenacyl-2-phenylpyrrolo [2.3-b]pyridine

3-(Cyanomethyl)-2-phenylpyrrolo[2,3-b]pyridine (0.35 g, 1.5 mmol) andphenacyl bromide (0.36 g) in acetonitrile (5 ml) was refluxed for 18 h.The resulting solid product was isolated by filtration and washed withdiethyl ether to give pure3-(cyanomethyl)-7-phenacyl-2-phenylpyrrolo[2,3-b]pyridine hydrobromide(0.46 g, 70%).

(¹ H-NMR, 300 MHz, DMSO-d₆). 4.40 (s, 2H), 6.68 (s, 2H), 7.56-74 (m,8H), 7.78-7.91 (m, 2H), 8.12 (d, 2H, J 7 Hz), 8.74 (d, 1H, J 6 Hz), 9.04(d, 1H, J 8 Hz).

Example 66

Preparation of 3-(carbamoylmethyl)-7-phenacyl-2-phenylpyrrolo[2.3-b]pyridine hydrobromide

3-(Carbamoylmethyl)-2-phenylpyrrolo[2,3-b]pyridine (0.35 g, 1.4 mmol)and phenacyl bromide (0.33 g) in acetonitrile (5 ml) were refluxed underargon for 3 h. The resulting yellow suspension was isolated byfiltration (0.4 g). The sparingly soluble raw product was dissolved in amixture of methanol (20 ml) and methylene chloride (480 ml), loaded on aflash chromatography column (SiO₂ /CH₂ Cl₂ :MeOH 96:4), and eluted witha) 1000 ml MeOH:CH₂ Cl₂ 2.5:97.5; b) 1000 ml MeOH:CH₂ Cl₂ 5:95; c) 1000ml MeOH:CH₂ Cl₂ 1:9 to afford pure3-(carbamoylmethyl)-7-phenacyl-2-phenylpyrrolo[2,3-b]pyridine which wasisolated as its hydrobromide (0.14 g, 22%).

(free base, ¹ H-NMr, 500 MHz, DMSO-d₆) 3.70 (s, 2H), 6.33 (s, 2H),6.68-7.71 (t, 2H, J 7 Hz), 7.27 (t, 1H, J 7.5 Hz), 7.37 (t, 2H, J 7.5Hz), 7.44 (br s, disappears on addition of D₂ O), 7.64 (t, 2H, J 8 Hz),7.77 (t, 1H, J 7 Hz), 7.89 (d, 2H, J 8 Hz), 8.01 (d, 1H, J 6 Hz), 8.17(D, 2H, J 7.5 Hz), 8.23 (d, 1H, J 7.5 Hz).

Example 67

5-Chloro-3-cyanomethyl-2-methyl-7-(2-phenyl-2-hydroxyethyl)pyrrolo[2,3-b]pyridine

The title compound was prepared from5-chloro-3-cyanomethyl-2-methyl-7-phenacylpyrrolo[2,3-b]pyridine(example 33) and NaBH₄ on a 0.33 mmol scale according to the proceduredescribed in example 11. Chromatography of the crude material (silica,CH₂ Cl₂ /MeOH; 96/4) afforded 45 mg (42%) pure product.

(¹ H-NMR, 300 MHz, CDCl₃). 2.54 (s, 3H), 3.78 (s, 2H), 4.67-4.90 (m,2H), 5.30 (m, 1H), 7.32 (coinciding signals, 6H), 7.95 (d, 1H).

Example 68

Preparation of3-cyanomethyl-2-methyl-7-(2,4-difluorophenacyl)pyrrolo[2,3-b]pyridine

The title compound was prepared from III and 2-chloro-2',4'-difluoroaceto-phenone on a 2.3 mmol scale according to the proceduredescribed in example 8 yielding 570 mg (68%).

(¹ H-NMR, 300 MHz, DMSO-d₆). 2.50 (s, 3H), 4.25 (s, 2H), 6.45 (m, 2H),7.40 (dr, 1H), 7.65 (dr, 1H), 7.75 (t, 1H), 8.10 (m, 1H), 8.55 (d, 1H),8.80 (d, 1H).

Example 69

Preparation of 3-cyanomethyl-2-methyl-7-(2-methoxyphenacyl)pyrrolo[2,3-b]pyridine

The title compound was prepared from III andw-bromo-2-methoxyacetophenone on a 4,2 mmol scale according to theprocedure described in example 8 yielding 0.9 g (54%).

(¹ H-NMR, 300 MHz, DMSO-d₆). 2,50 (s, 3H), 4.10 (s, 3H), 4.25 (s, 2H),6.25 (s, 2H), 7.15 (t, 1H), 7.40 (d, 1H), 7.75 (m, 2H), 7.90 (dd, 1H),8.60 (d, 1H), 8.80 (d, 1H).

Example 70

Preparation of3-cyanomethyl-2-methyl-7-(2-hydroxyphenacyl)pyrrolo[2,3-b]pyridine

To a deaerated solution of the compound according to example 69 (3.6 g,8.9 mmol) in 60 ml CH₂ Cl₂ 10.6 ml of 1M BBr₃ in CH₂ Cl₂ (10,6 mmol) wasadded dropwise. The solution was stirred at room temperature for 3h andwas then poured into 50 ml of 1 m NaHCO₃. The water layer was extractedthree times with 100 ml CH₂ Cl₂ and the combined organic layers waswashed once with 100 ml 2 m HCl. The organic layer was dried over Na₂SO₄ and evaporated. The residue was recrystallized from CH₃ CN affording2,2 g (73%).

(¹ H-NMR, 500 MHz, DMSO-d₆). 2.50 (s, 3H), 4.25 (s, 2H), 6.35 (s, 2H),7.00 (t, 1H), 7.20 (d, 1H), 7.60 (t, 1H), 7.70 (t, 1H), 7.85 (d, 1H),8.60 (d, 1H), 8.75 (d, 1H).

Example 71

Preparation of3-cyanomethyl-5-fluoro-2-methyl-7-[4-fluorophenacyl)pyrrolo[2,3-b]pyridinehydrochloride

A mixture of 3-(cyanomethyl)-5-fluoro-2-methylpyrrolo[2,3-b]pyridine(10mg, 0.053 mmol) and 4-fluorophenacyl chloride (19 mg, 0.11 mmol) inacetonitrile (0.2 ml) was refluxed under argon for 26 h, during whichtime the initial solution was transformed into a suspension. Then thesuspension was allowed to reach room temperature, diluted with diethylether (2ml), and filtered. The crystalline product was washed withdiethyl ether to give 8 mg (42%) of the title compound.

(¹ H-NMR, 500 MHz, CD₃ OD) 8.77 (dd, 1H, J₁ 8 Hz, J₂ 2 Hz), 8.66 (m,1H), 8.23 (m, 2H), 7.39 (t, 1H, J 8.5 Hz), 6.47 (s, 2H), 4.12 (s, 2H),2.57 (s, 3H).

Example 72

Preparation of3-cyanomethyl-5-fluoro-2-methyl-7-((2,4-difluorophenacyl)phenacyl)pyrrolo[2,3-b]pyridinehydrochloride

The title compound was prepared from3-(cyanomethyl)-5-fluoro-2-methylpyrrolo[2,3-b]pyridine (10 mg, 0.053mmol) and 2,4-difluorophenacyl chloride (128 mg, 0.67 mmol) inacetonitrile (0.2 ml) in the same fashion as described in example 71;yield 16 mg (80%).

(¹ H-NMR, 500 MHz, CD₃ OD) 8.77 (dd, 1H, J₁ 7.5Hz, J₂ 1.5Hz) , 8.65 (m,1H) , 8.16 (m, 1H) , 8.07 (m, 1H) , 7.33 (m, 1H), 7.23 (m, 1H), 6.32 (s,2H), 4.12 (s, 2H), 2.57 (s, 3H).

Example 73

Preparation of3-cyanomethyl-5-fluoro-2-methyl-7-(2-methoxyphenacyl)pyrrolo[2,3-b]pyridinehydrobromide

A mixture of 3-(cyanomethyl)-5-fluoro-2-methylpyrrolo[2,3-b]pyridine (20mg, 0.11 mmol) and 2-methoxyphenacyl bromide (30 mg, 0.13 mmol) inacetonitrile (0.2 ml) was refluxed under argon for 6 h, during whichtime the initial solution was transformed into a suspension. Then thesuspension was allowed to reach room temperature, diluted with diethylether (2 ml), filtered, and washed with diethylether to give 36 mg (81%)of the title compound.

(¹ H-NMR, 500 MHz, CD₃ OD) 8.74 (dd, 1H, J₁ 8 Hz, J₂ 2 Hz,), 8.68 (m,1H), 8.00 (dd, 1H, J₁ 8 Hz J₂ 2 Hz), 7.73 (m, 1H), 7.34 (d, 1H, J 8 Hz),7.12 (t, 1H, J 7.5 Hz), 6.29 (s, 2H), 4.15 (s, 3H), 4.12 (s, 2H), 2.56(s, 3H).

Example 74

Preparation of3-cyanomethyl-5-fluoro-2-methyl-7-(2-hydroxyphenacyl)pyrrolo[2,3-b]pyridine

A mixture of3-cyanomethyl-5-fluoro-2-methyl-7-(2-methoxyphenacyl)pyrrolo[2,3-b]pyridinehydrobromide (25 mg, 0.06 mmol), methylene chloride (2 ml), and BBr₃ inmethylene chloride (1M; 0.4 ml) under argon was refluxed for 8 h. Thered gum was digested in a methylene chloride aqueous sodium bicarbonatemixture. The organic phase was dried over anhydrous Na₂ SO₄, filtered,and evaporated to give a yellow crystalline product. Yield 19 mg (98%).

(¹ H-NMR, 500 MHz, CD₃ OD) 8.17 (dd, 1H, J₁ 8.5 Hz, J₂ 2 Hz), 8.09 (m,1H), 7.98 (dd, 1H, J₁ 8 Hz, J₂ 1.5 Hz), 7.57 (m, 1H), 7.02 (m, 2H), 3.96(s, 2H), 3.34 (s, 2H), 2.46 (s, 3H).

The following Table 1 gives illustrative examples of compounds of theinvention

                                      TABLE 1                                     __________________________________________________________________________    Illustrative compounds of the invention                                        ##STR20##                                                                    Example No.                                                                          X      R1              R.sup.2 R.sup.3 R.sup.4                                                                              R.sup.5                                                                            Yield               __________________________________________________________________________                                                              %                    1     CH.sub.2                                                                             CH.sub.3        H       H       H      H    62                   2     CH.sub.2                                                                             CH.sub.3        Cl      H       H      H    50                   3     CH.sub.2                                                                             CH.sub.3        CH.sub.2 CN                                                                           H       H      H    25                   4     CH.sub.2                                                                             H               CH.sub.3                                                                              H       H      H    27                   5     CH.sub.2                                                                             CH.sub.2 OH     CH.sub.3                                                                              H       H      H    13                   6     CH.sub.2                                                                             Cl              CH.sub.3                                                                              H       H      H    18                   7     CH.sub.2                                                                             CH.sub.3        CH.sub.3                                                                              6-NH.sub.2                                                                            H      H     6                   8     CO     CH.sub.3        CH.sub.3                                                                              H       H      H    69                   9     CO     CH.sub.3        Cl      H       H      H    67                  10     CO     CH.sub.3        CH.sub.3                                                                              H       4'-Br  H    92                  11     CHOH   CH.sub.3        CH.sub.3                                                                              H       H      H    94                  12     CHOH   CH.sub.3        Cl      H       H      H    19                  13     CHOH   CH.sub.3        CH.sub.3                                                                              H       4'-CN  H    61                  14     CO     CH.sub.3        H       H       H      H    88                  15     CO     CH.sub.3        CH.sub.3                                                                              H       2'-CF.sub.3                                                                          H    36                  16     CO     CH.sub.3        Br      H       H      H    37                  17     CO     Cl              CH.sub.3                                                                              H       H      H    65                  18     CHOH   Cl              CH.sub.3                                                                              H       H      H    84                  19     CO     CH.sub.3        OCH.sub.3                                                                             H       H      H    34                  20     CO     CH.sub.2 OCH.sub.3                                                                            CH.sub.3                                                                              H       H      H    20                  21     CO     Cl              CH.sub.3                                                                              H       4'-F   H    57                  22     CHOH   Cl              CH.sub.3                                                                              H       4'-F   H    99                  23     CO     Cl              CH.sub.2 CN                                                                           H       H      H     9                  24     CO     CH.sub.3        CH.sub.3                                                                              H       2'-SCH.sub.3                                                                         H    20                  25     CO     CH.sub.3        HO      H       H      H    23                  26     CO     CH.sub.3        CH.sub.3                                                                              5-CF.sub.3                                                                            H      H    15                  27     CO     CH.sub.3        CH.sub.3                                                                              H       4'-CN  H    85                  28     CO     CH.sub.3        CH.sub.3                                                                              H       4'-F   H    64                  29     CO     CH.sub.3        CH.sub.3                                                                              H       4'-OCH.sub.3                                                                         H    73                  30     CO     CH.sub.3        CH.sub.3                                                                              H       3'-OCH.sub.3                                                                         H    70                  31     CO     CH.sub.3        CH.sub.3                                                                              H       2'-OCH.sub.3                                                                         H    71                  32     CO     CH.sub.3        CH.sub.3                                                                              H       2'-F   4'-F 56                  33     CO     CH.sub.3        CH.sub.2 CN                                                                           5-Cl    H      H    91                  34     CHOCH.sub.3                                                                          CH.sub.3        CH.sub.3                                                                              H       H      H    65                  35     CO     CH.sub.3        CH.sub.3                                                                              H       2'-NO.sub.2                                                                          H    66                  36     CO     CH.sub.3        CH.sub.3                                                                              H       2'-NH.sub.2                                                                          H    46                  37     CO     CH.sub.3        CH.sub.3                                                                              H       4'-CH.sub.3                                                                          H    74                  38     CHOH   CH.sub.3        CH.sub.3                                                                              H       H      H    92                  39     CHOH   CH.sub.3        CH.sub.3                                                                              H       H      H    82                  40     CO     CH.sub.3        CH.sub. 3                                                                             H       2'-OH  H    62                  41     CH.sub.2                                                                             CH.sub.3        CH.sub.3                                                                              6-SCH.sub.3                                                                           H      H    13                  42     CH.sub.2                                                                             CH.sub.3        CH.sub.3                                                                              6-SCH.sub.2                                                                           H      H    26                                                        CH.sub.2 C.sub.6 H.sub.5                43     CO     CH.sub.3        CH.sub.3                                                                              6-SCH.sub.3                                                                           H      H    35                  44     CO     CH.sub.3        CH.sub.3                                                                              5-SCH.sub.3                                                                           H      H    63                  45     CO     CH.sub.3        CH.sub.3                                                                              5-SOCH.sub.3                                                                          H      H    41                  46     CH.sub.2                                                                             CH.sub.3        CH.sub.3                                                                              H       2'-COOH                                                                              H    23                  47     CO     CH.sub.3        CH.sub.3                                                                              5-Br    H      H    72                  48     CO     CH.sub.3        CH.sub.3                                                                              5-CN    H      H    26                  49     CO     CH.sub.3        CH.sub.2 CN                                                                           H       H      H    58                  50     CO     CH.sub.3                                                                                       ##STR21##                                                                            H       H      H    39                  51     CO     CH3             CH.sub.2 CN                                                                           H       4'-F   H    55                  52     CH.sub.2                                                                             CH.sub.3        CH.sub.3                                                                              H       2'-NHCOCH.sub.3                                                                      H     8                  53     CO     CH.sub.3        CH.sub.3                                                                              H       2'-F   6'                                                                                 54                  54     CO     CH.sub.3        SCN     H       H      H    23                  55     CO                                                                                    ##STR22##      CH.sub.3                                                                              H       H      H    74                  56     CO                                                                                    ##STR23##      CH.sub.3                                                                              H       H      H    46                  57     CO                                                                                    ##STR24##      CH.sub.3                                                                              H       H      H    30                  58     CO                                                                                    ##STR25##      CH.sub.3                                                                              H       H      H    97                  59     CO                                                                                    ##STR26##      CH.sub.3                                                                              H       H      H    96                  60     CO                                                                                    ##STR27##      CH.sub.3                                                                              H       H      H    92                  61                                                                            isom1  CNOCH.sub.3                                                                          CH.sub.3        CH.sub.3                                                                              H       H      H    60                  isom2  CNOCH.sub.3                                                                          CH.sub.3        CH.sub.3                                                                              H       H      H    21                  62     CHOH   Cl              CH.sub.2 CN                                                                           H       H      H    46                  63     CO     CH.sub.3        CH.sub.2 CN                                                                           5-F     H      H    90                  64     CO                                                                                    ##STR28##      CH.sub.3                                                                              5-Br    H      H    73                  65     CO                                                                                    ##STR29##      CH.sub.2 CN                                                                           H       H      H    70                  66     CO                                                                                    ##STR30##      CH.sub.2 CONH.sub.2                                                                   H       H      H    22                  67     CHOH   CH.sub.3        CH.sub.2 CN                                                                           5-Cl    H      H    42                  68     CO     CH.sub.3        CH.sub.2 CN                                                                           H       2'-F   4'-F 68                  69     CO     CH.sub.3        CH.sub.2 CN                                                                           H       2'-OCH.sub.3                                                                         H    54                  70     CO     CH.sub.3        CH.sub.2 CN                                                                           H       2'-OH  H    73                  71     CO     CH.sub.3        CH.sub.2 CN                                                                           5-F     4'-F   H    42                  72     CO     CH.sub.3        CH.sub.2 CN                                                                           5-F     2'-F   4'-F 80                  73     CO     CH.sub.3        CH.sub.2 CN                                                                           5-F     2'-OCH.sub.3                                                                         H    81                  74     CO     CH.sub.3        CH.sub.2 CN                                                                           5-F     2'-OH  H    98                  75     CHOH   Cl              CH.sub.2 CN                                                                           5-OH    H      H                        76     CO     Cl              CH.sub.3                                                                              5-F     H      H                        77     CO     Cl              CH.sub.3                                                                              5-F     2'-F   4'-F                     78     CO     Cl              CH.sub.3                                                                              5-OCH.sub.3                                                                           H      H                        79     CHOH   Cl              CH.sub.3                                                                              5-OH    2'-F   4'-F                     80     CO     Cl              CH.sub.3                                                                              6-CH.sub.2 OCH.sub.3                                                                  H      H                        81     CHOH   Cl              CH.sub.3                                                                              6-NH.sub.2                                                                            H      H                        82     CO     Cl              CH.sub.3                                                                              6-NHCOCH.sub.3                                                                        H      H                        83     CO     Cl              CH.sub.2 OH                                                                           H       H      H                        84     CO     CH.sub.3        CF.sub.3                                                                              H       H      H                        85     CHOH   Cl              CH.sub.2 C CH                                                                         H       H      H                        86     CO     CH.sub.3        CH.sub.2 CN                                                                           5-OCH.sub.3                                                                           H      H                        87     CO     CH.sub.3        NH.sub.2                                                                              5-F     H      H                        88     CHOH   Cl              CH.sub.3                                                                              5-OCH.sub.3                                                                           H      H                        89     CHOH   Cl              CH.sub.3                                                                              5-F     H      H                        90     CHOH   CH.sub.3        CH.sub.2 CN                                                                           5-F     H      H                        91     CHOH   CH.sub.3        CH.sub.2 CN                                                                           5-F     4'-F   H                        92     CHOH   CH.sub.3        CH.sub.2 CN                                                                           5-F     2'-OCH.sub.3                                                                         H                        93     CHOH   CH.sub.3        CH.sub.2 CN                                                                           5-F     2'-OH  H                        94     CHOH   CH.sub.3        CH.sub.2 CN                                                                           5-F     2'-F   4'-F                     95     CH.sub.2                                                                             CH.sub.3        CH.sub.2 CN                                                                           5-F     2'-OCH.sub.3                                                                         H                        96     CH.sub.2                                                                             CH.sub.3        CH.sub.2 CN                                                                           5-F     2'-OH  H                        97     CH.sub.2                                                                             CH.sub.3        CH.sub.2 CN                                                                           5-F     2'-F   4'-F                     98     CH.sub.2                                                                             CH.sub.3        CH.sub.2 CN                                                                           5-F     4'-F   H                        99     CH.sub.2                                                                             CH.sub.3        CH.sub.2 CN                                                                           5-F     H      H                        100    CHOCH.sub.3                                                                          CH.sub.3        CH.sub.2 CN                                                                           5-F     H      H                        101    CHOCH.sub.3                                                                          CH.sub.3        CH.sub.2 CN                                                                           5-F     2'-F   4'-F                     102    CHOCH.sub.3                                                                          CH.sub.3        CH.sub.2 CN                                                                           5-F     4'-F   H                        103    CHOCH.sub.3                                                                          CH.sub.3        CH.sub.2 CN                                                                           5-F     2'-OCH.sub.3                                                                         H                        104    CHOCH.sub.3                                                                          CH.sub.3        CH.sub.2 CN                                                                           5-F     2'-OH  H                        __________________________________________________________________________

The following examples illustrate intermediates useful in thepreparation of compounds exemplified in the examples

Example I

Preparation of 3-[(dimethylamino)methyl]-2-methylpyrrolo[2,3-b]pyridine

A solution of 200 mg (1.5 mmol) 2-methyl-pyrrolo[2,3-b]pyridine 200 mg(2.5 mmol) dimethylaminhydrochloride and 73 mg (2.5 mmol)paraformaldehyde in 2,5 ml methanol was refluxed for four days. Thereaction mixture was cooled to room temperature and the solvent wasevaporated under reduced pressure. To the residue was added 2 ml waterand ml methylene chloride and the pH was adjusted to 11 with 2 M sodiumhydroxide. The organic layer was washed once with water dried oversodium sulfate and the solvent was evaporated to give 0.17 g (60%) oftitle compound.

(¹ H-NMR, 500 MHz, CDCl₃). 2.25(s,6H), 2.50(s,3H), 3.55(s,2H), 7.03(dd,1H), 7.92 (d, 1H), 8.01/dd, 1H).

Example II

Preparation of 3-[(trimethylamino)methyl]pyrrolo[2,3-b]pyridine.

A solution of 163 mg (0.86 mmol) of Example I and 135 mg (0.95 mmol) ofmethyliodide in 1 ml ethanol were stirred for 40 hours at roomtemperature. The solvent was evaporated and the crude product 270 mg(95%) was used directly in the next step.

(¹ H-NMR, 500 MHz, DMSO-d₆). 3.10(s,9H), 3.30(s,3H), 4.62(s,2H),7.12(dd, 1H), 8.08(d, 1H), 8.19(d, 1H).

Example III

Preparation of 3-cyanomethyl-2-methylpyrrolo[2,3-b]pyridine

To a solution of 270 mg (0.82 mmol) of Example II in 2,5 mldimethylformamide was added 44 mg (0.90) mmol of sodium cyanide andheated at 100° C. for 1.5 hours with stirring the reaction mixture wascooled to room temperature and partitioned between water and methylenechloride. The organic layer was dried over sodium sulfate and thesolvent was evaporated to give 130 mg (98%) of the title compound.

(¹ H-NMR, 500 MHz, CDCl₃). 2.53(s,3H), 3.77(s,2H), 7.12(dd, 1H),7.92(dd, 1H), 8.27(dd, 1H).

Example IV

Preparation of 3-chloro-2-methylpyrrolo[2,3-b]pyridine

To a solution of 0,7 g (5.3 mmol) of 2-methylpyrrolo[2,3-b]pyridine in2,5 ml glacial acetic acid was added dropwise 0,8 g (5.9 mmol) ofsulfuryl chloride at room temperature and with stirring. The reactionmixture was stirred for 1 hour. The solvent was evaporated and theresidue was partitioned between methylene chloride and a saturatedsodium bicarbonate solution. The organic layer was dried over sodiumsulfate and the solvent was evaporated. The residue was crystallizedfrom ether: ethyl acetate, 5:1 to give 0,45 g (51%) of the titlecompound.

(¹ H-NMR, 500 MHz, CDCl₃). 2.50(s,3H), 7.12(dd, 1H), 7.84 (dd, 1H),8.25(dd, 1H).

Example V

Preparation of 2-hydroxymethyl-3-methylpyrrolo[2,3-b]pyridine

2,3-dimethylpyrrolo[2,3-b]pyridine(0,2 g 0.0014 mol) was treated in 3 mlacetic acid with an equimolecular amount of bromine and after 5 minyellow precipitate was formed. The solid was filtered off and treatedwith 3 ml water for 60 min. The mixture was made alkaline withbicarbonate and extracted with methylene chloride. When the organiclayer had been dried and evaporated the product was isolated as a yellowoil. (0,12 g, 53%).

(¹ H-NMR, 300 MHz, CDCl₃). 2.2(s,3H), 4.7(s,2H), 7.0(dd, 1H), 7.8(dd,1H), 8.25(dd, 1H).

Example VI

Preparation of 2-chloro-3-methylpyrrolo[2,3-b]pyridine

3-methylpyrrolo[2,3-b]pyridine (0,5 g 0.0038 mol) was treated in 2 mlacetic acid with an equimolecular amount of sulfuryl chloride at 0° C.for 5 min. The mixture was allowed to warm to room temperature and wasstirred for 5 min. After evaporation the residue was dissolved inmethylene chloride and was treated with bicarbonate. The organic layerwas separated, dried and removed under reduced pressure. Chromatographyon silica gel eluting with ethyl acetate gave the desired product. (0,18g 29%).

(¹ H-NMR, 300 MHz, CDCl₃). 2.25(s,3H), 7.05(dd,1H), 7.75(dd,1H),8.25(dd, 1H).

Example VII

Preparation of 2,3-dimethyl-5-trifluoromethylpyrrolo[2,3-b]pyridine

A mixture of 2-chloro-5-trifluoromethylpyridine (10 g 0.055 mol) andhydrazine mono hydrate (2,7 g, 0.055 mol) in 35 ml n-propanol wasrefluxed for 2 h and was then stirred 20 h at RT. To the solution wasadded 4,35 g (0.06 mol) methylethylketon and the mixture was refluxedfor 30 min. After the solvent was removed under reduced pressure theresidue was partitioned between methylene chloride and bicarbonatesolution. The organic layer was dried over Na₂ SO₄ and evaporated. Theresidue was solved in 80 ml diethylene glycol and refluxed for 5 h. Thereaction mixture was poured into ice-water and extracted with methylenechloride. The organic layer was separated dried over Na₂ SO₄ andevaporated. The residue was treated with warm petroleumether (60-80 )wich was decantated and evaporated chromatography twice on silica gelwith 1 methylene chloride/methanol 2 ethyl acetate, gave the desiredproduct. (0,2 g 1.7% ).

(¹ H-NMR, 300 MHz, CDCl₃). 2.3(s,3H), 2.45(s,3H), 8.0(s,1H), 8.5 (s,1H).

Example VIII

Preparation of 3-methoxy-2-methylpyrrolo[2,3-b]pyridine.

A solution of 7,4 g (68 mmol) 2-hydrazinopyridine and 6,0 g (68 mmol)methoxyaceton in 50 ml of ethanol was refluxed for 1 h. The solvent wasremoved under reduced pressure. The resulting oil was dissolved indiethylene glycol and refluxed for 1,5 h. The mixture was allowed tocool and was poured into ice-water. Extraction with methylene chloridegave an black oily residue which was treated with boiling petroleumether(60-80). After decanting the solvent was allowed to cool and theprecipitated product filtered of affording 4,5 g (41%) pure titlecompound as a yellow solid.

(¹ H-NMR, 300 MHz, CDCl₃). 2.45(s,3H), 3.9(s,3H), 7.0(t,1H), 7.85 (d,1H), 8.15 (d, 1H).

Example IX

2-Chloro-3-cyanomethylpyrrolo[2,3-b]pyridine.

3-cyanomethylpyrrolo[2,3-b]pyridine (1,55 g, 0.098 mol) was treated in 5ml acetic acid with an equimolecular amount of sulfurylchloride at 0° C.for 5 min. The mixture was allowed to warm to room temperature and wasstirred 5 min. After evaporation the residue was dissolved in methylenchloride and was treated with bicarbonate. The organic layer wasseparated, dried over Na₂ SO₄ and the solvent was removed under reducedpressure. Chromatography on silica gel eluting with ethyl acetate gavethe desired product. (0,4 g 21%).

(¹ H-NMR, 500 MHz, CDCl₃). 3.85(s,2H), 7.2(t,1H), 8.05(d, 1H), 8.4(d,1H).

Example X

2-Methoxymethyl-3-methylpyrrolo[2,3-b]pyridine.

2,3-dimethylpyrrolo[2,3-b]pyridine 0,5 g (0.0034 mol) was treated in 7ml acetic acid with an equimolecular amount of bromine and after 5 min ayellow precipitate was formed. The solid was filtred off and treatedwith 20 ml methanol. The mixture was refluxed for 30 min. and was thenevaporated. The residue was partitioned between methylene chloride andbicarbonate solution. The organic layer was separated dried over Na₂ SO₄and evaporated. The residue was treated with boiling petroleumether(60-80) which was decantated and allowed to cool. The precipitatedproduct was filtred off affording 0,13 g (22%) as white solid.

(¹ H-NMR 300 MHz CDCl₃). 2.3(s,3H), 3.4(s,3H), 4.65(s,2H), 7.05(dd, 1H),7.85(d, 1H), 8.3(d, 1H).

Example XI

Preparation of 6-bromo-2,3-dimethyl-pyrrolo[2,3-b]pyridine

A mixture of 2,6-dibromopyridine (47.4 g, 0.3 mol) and hydrazine monohydrate (97.2 ml, 2.0 mol) in 400 ml propanol was refluxed for 19 h. Thesolvent was evaporated and the residue taken up in 1000 ml CH₂ Cl₂. Theorganic layer was washed with 500 ml 5% Na₂ CO₃ (reextraction with500+250+250 ml CH₂ Cl₂), dried over MgSO₄, and evaporated. The residuewas recrystallized from 100 ml abs. EtOH leaving 30.0 g2-bromo-6-hydrazinopyridine. Reprocessing of the mother liquor gaveadditional 2.5 g. Yield 32,5 g (87%).

A suspension of 2-bromo-6-hydrazinopyridine (32,5 g, 0.17 mol) in absEtOH was treated with ethyl methyl ketone (20 ml, 0.22 mol) for 1 h atreflux. The reaction mixture was allowed to cool and treated withadditional ethyl methyl ketone (10+3+1 ml) until all starting materialhad dissapeared according to TLC. The reaction mixture was taken up in150 ml diethylene glycol and the EtOH evaporated at reduced pressure at70° C. The remaining solution was deaerated and heated to reflux for22h. The reaction mixture was cooled and paritioned between 1250 ml CH₂Cl₂ and 1000 ml 2M HCl (reextracted with 250 ml CH₂ Cl₂). The organiclayer was washed with further 500 ml 2M HCl and 500 ml H₂ O dried overMgSO₄, and evaporated. Chromatography (silica, CH₂ Cl₂ /diethyl ether;95/5) afforded 6 g 6-bromo-2,3-dimethyl-pyrrolo[2,3-b] pyridine.Recrystallization from 120 ml abs EtOH gave 4,2 g (11%). (¹ H-NMR, 500MHz, CDCl₃) 2.19(s,3H), 2.42(s,3H), 7.16(d, 1H), 7.59(d, 1H), 9.12(b,1H).

Example XII

Preparation of 2,3-dimethyl-6-methylthiopyrrolo[2,3-b]pyridine

A deaerated solution of 6-bromo-2,3-dimethyl-pyrrolo [2,3-b]pyridine(225 mg, 1.0 mmol) in 25 ml dry THF was cooled to -78° C. and treatedwith 1.6M n-BuLi in hexane (1,5 ml, 2.4 mmol). The reaction mixture wasbrought to 0° C. and the lithiate trapped with dimethyl disulfide (444μl, 5 mmol). After reacting for 5 min 1.5 ml H₂ O was added and the THFevaporated. The residue was taken up in 100 ml CH₂ Cl₂ and washed with50 ml 5% NaHCO₃, 50 ml 2M HCl (reextracted twice with 25 ml CH₂ Cl₂),and 50 ml 5% NaHCO₃. The organic layer was dried over MgSO₄ andevaporated leaving 160 mg (83%) pure2,3-dimethyl-6-methylthio-pyrrolo[2,3-b]pyridine.

(¹ H-NMR, 500 MHz, CDCl₃) 2.17(d,3H), 2.36(s,3H), 2.60(s,3H),6.94(d,1H), 7.58(d,1H), 8.42(b,1H).

Example XIII

Preparation of 3-thiocyano-2-methylpyrrolo[2,3-b]pyridine

To a solution of 300 mg (2.36 mmol) of 2-methylpyrrolo[2,3-b]pyridineand 920 mg (11.3 mmol) of sodium thiocyanate in 5 ml acetic acid wasadded 450 mg (2.8 mmol) bromine in 1 ml acetic acid at 5° C. Thereaction mixture was stirred for 30 min at 5° C. and thereafter for 16 hat room temperature. The solid was filtered off. To the filtrate wasadded 20 ml water. The precipitated product was filtered off and washedwith water giving 160 mg (37%) of the title compound.

(¹ H-NMR 300 MHz DMSO-d₆). 2.55(s,3H), 7.22(dd, 1H), 7.97(dd, 1H),8.28(dd, 1H), 12.5(s,1H).

Example XIV

Preparation of 3-(1-pyrazolo)methyl-2-methypyrrolo[2,3 -b]pyridine

To a solution of 95 mg (0.29 mmol) of3[(trimethylammo-nio)-methyl]-pyrrolo[2,3-b]pyridine in 1,0 mldimethylformamide was added 24 mg (0.35 mmol) of pyrazole and heated at100° C. for 1.5 hours with stirring. The reaction mixture was cooled toroom temperature and partitioned between water and methylene chloride.The organic layer was dried over sodium sulfate and the solvent wasevaporated to give 30 mg (48%) of the title compound.

¹ H NMR (300 MHz, CDCl₃). 2.55(s,3H), 5.45(s,2H), 6.20(m,1H),7.03(m,1H), 7.52(m,1H), 7.62(d,1H), 7.7(m,1H), 8.21(m,1H).

Example XV

5-Cyano-2,3-dimethyl-pyrrolo[2,3-b]pyridine

An autoclave was charged with5-bromo-2,3-dimethyl-pyrrolo[2,3-b]pyridine (prepared in a similarmanner as 6-bromo-2,3-dimethyl-pyrrolo[2,3-b]pyridine (247 mg, 1.1 mmol)and CuCN (135 mg. 1.5 mmol). The mixture was covered with pyridine andheated to 220° C. for 12 h. After cooling the raction mixture was pouredinto a mixture of FeCl₃ hexahydrate (0.9 g), conc HCl (0.5 ml), andwater (10 ml). The mixture was heated to 80° C. for 1 h and extractedwith CH₂ Cl₂. The organic layer was washed four times with 2M HCl, driedover MgSO₄ and evaporated leaving 77 mg (40%)5-cyano-2,3-dimethyl-pyrrolo[2,3-b]pyridine.

(¹ H-NMR, 300 MHz, DMSO-d₆) 2.18(s,3H), 2.35(s,3H), 8.32 (d, 1H),8.45(d, 1H).

Example XVI

5-Chloro-3-cyanomethyl-2-methyl-pyrrolo[2,3-b]pyridine

A mixture of 2,5-dichloropyridine (10.7 g, 0.07 mol) and hydrazine monohydrate (34.0 ml, 0.7 mol) in 140 ml propanol was refluxed for 17h. Thesolvent was evaporated and the residue taken up in 500 ml CH₂ Cl₂. Theorganic layer was washed with 200 ml 5% NaHCO₃ (reextraction with 100 mlCH₂ Cl₂), dried over MgSO₄, and evaporated. The residue wasrecrystallized from 17 ml abs. EtOH leaving 4.7 g5-chloro-2-hydrazinopyridine. Reprocessing of the mother liquor gaveadditional 0.1 g. Yield 4.8 g (48%). A mixture of5-chloro-2-hydrazinopyridine (4.9 g, 34 mmol) and α-(methylthio)acetone(3.5 g, 34 mmol) in 10 ml abs EtOH was heated to reflux. The reactionmixture was allowed to cool and taken up in 30 ml diethylene glycol. TheEtOH was evaporated at reduced pressure at 70° C. and the remainingsolution deaerated and heated to reflux for 1.5h. The reaction mixturewas cooled and taken up in 500 ml CH₂ Cl₂. The organic layer was washedtwice with 400 ml H₂ O (each portion was reextracted with 100 ml CH₂Cl₂), dried over MgSO₄, and evaporated. The residue was filtered throughsilica eluting with CH₂ Cl₂. Fractions containing product were pooled, asmall volume of abs EtOH was added, and the CH₂ Cl₂ evaporated. Theprecipitated 5-chloro-2-methyl-3-methylthio-pyrrolo[2,3-b]pyridine wascollected and washed with a small volume of ligroine affording 1.5 g(20%) pure product. Reprocessing of the mother liquour gave additonalmaterial, 1.0 g (14%).

A deaerated solution of5-chloro-2-methyl-3-methylthiopyrrolo[2,3-b]pyridine (1.1 g, 5.0 mmol)in 45 ml 1,4-dioxane was heatet to 70° C. and treated with smallportions of Raney-Ni until all starting material had disappearedaccording to GC-MS,(total reaction time: 48h). The catalyst was filteredoff and washed with several portions of 5% Na₂ CO₃. Pure5-chloro-2-methyl-pyrrolo[2,3-b]pyridine appeared as a white precipitatein the filtrate and was collected. A second lot was obtained afterevaporating the filtrate, dissolving it in 2M HCl, and carefullybasifying the solution with Na₂ CO₃. Yield 0.6 g (74%).

A mixture of 5-chloro-2-methyl-pyrrolo[2,3-b]pyridine (514 mg, 3.1mmol), paraformaldehyde (102 mg, 3.4 mmol), and dimethylamoniumhydrochloride (277 mg, 3.4 mmol), in 12 ml butanol was refluxed for1.5h. Most of the solvent was evaporated and the remaining moist residuetreated with ice cold diethyl ether. The precipitate was collected anddried leaving 707 mg (93%) of a 1:1 mixture of5-chloro-3-dimethylaminomethyl-2-methyl-pyrrolo[2,3-b]pyridine and thecorresponding hydrochloride.

A 1:1 mixture of5-chloro-3-dimethylaminomethyl-2methylpyrrolo[2,3-b]pyridine and thecorresponding hydrochloride (674 mg, 140 mmol) and conc HCl (1.16 ml,140 mmol) each 12 h until all starting material had disappearedaccording to DI-MS. The reaction mixture was taken up in 200 ml 5% Na₂CO₃ and extracted twice with 200 ml CH₂ Cl₂. The combined organic layerswere dried over MgSO₄ and evaporated leaving 147 mg (26%) pure5-chloro-3-cyanomethyl-2-methyl-pyrrolo[2,3-b]pyridine.

(¹ H-NMR, 500 MHz, CDCl₃) 2.51(s,3H), 3.72(s,2H), 7.87(d,1H),8.21(d,1H), 9.16(b,1H).

Example XVII

2-(p-Bromophenyl)-3-methyl-pyrrolo[2,3-b]pyridine

A mixture of 2-hydrazinopyridine (11.1 g, 0.10 mol) andp-bromopropiophenone (25 g, 0.12 mol) in 85 ml 95% EtOH was refluxed for12 h. Evaporation of the solvent afforded a quantitative yield of thecorresponding hydrazone. (DI-ms, EI at 70 ev) m/z 303 (5), 274 (70), 183(100), 155 (65).

The residue was dissolved in 100 ml DEG, deaerated and violentlyrefluxed in a nitrogen atmosphere for 6 h. The reaction mixture wasallowed to cool and poured into 700 ml H₂ O. The precipitated productwas collected and recrystallized from EtOH affording 6.48 g (22%) of thedesired product.

(¹ H-NMR, 300 MHz, CDCl₃). 2.45 (s, 3H), 7.10 (dd, 1H), 7.50 (d, 2H),7.65 (d, 2H), 7.90 (dd, 1H), 8.25 (d, 1H).

Example XVIII

2-(p-Carboxyphenyl)-3-methyl-pyrrolo[2,3-b]pyridine

2-(p-Bromophenyl)-3-methyl-pyrrolo-[2,3 -b]pyridine (1 g, 3.5 mmol) wasdissolved in 200 ml dry THF, deaerated and cooled to -78° C.n-Butyllithium (5.19 ml, 8.4 mmol) was added dropwise and the mixturewas allowed to reach room temperature CO₂ (g) was bubbled through thesolution for 10 min.

Excess of n-butyllithium was destroyed with a small amount of water. Thesolvent was evaporated and the residue partitioned between 100 ml CH₂Cl₂ and 100 ml 5% Na₂ CO₃. The water layer was acidified (pH 2) with 2MHCl. The precipitated product was filtred off and dried affording 0.38 g(44%) of the title compound.

(¹ H-NMR, 300 MHz, D₂ O). 2.35 (s, 3H), 7.15 (bs, 1H), 7.65 (d, 2H),7.95 (m, 3H), 8.20 (bs, 1H).

Example XIX

p-[3methyl-pyrrolo[2,3-b]-pyridine-2]yl-benzoylchloride

2-(p-Carboxyphenyl)-3-methyl-pyrrolo-[2,3b]pyridine (1 g, 4 mmol) wasdissolved in 20 ml thionyl chloride at 0° C. The solution was allowed toreact at room temperature for 2 h. The solvent was evaporated. Theresidue was evaporated twice with CH₂ Cl₂ to remove excess of thionylchloride to give quantitative yield of the title compound.

(¹ H-NMR, 300 MHz, CDCl₃). 2.50 (s, 3H), 7.40 (t, 1H), 7.80 (d, 2H),8.20 (m, 3H), 8.40 (d, 1H).

Example XX

methyl-[p-(3-methyl-pyrrolo[2,3-b]-pyridine)-2]yl benzoate

p-[3-methyl-pyrrolo[2,3 -b]-pyridine-2]yl benzoylchloride (0.41 g, 1.5mmol) was chromatographed on silica gel (CH₂ Cl₂ : MeOH, 95:5) to give0.28 g (69%) of the title compound.

(¹ H-NMR, 300 MHz, CDCl₃). 2.50 (s, 3H), 3.95 (s, 3H), 7.10 (dd, 1H),7.75 (d, 2H), 7.95 (d, 1H), 8.15 (d, 2H), 8.20 (d, 1H).

Example XXI

Isopropyl-[p(3-methyl-pyrrolo[2,3-b]pyridine)-2]yl benzoate

p-[3-Methyl-pyrrolo[2,3-b]-pyridine-2]yl benzoylchloride (1.1 g, 4 mmol)was dissolved in 20 ml CH₂ Cl₂. 2-Propanol (1.20, 20 mmol) andtriethylamine (0.4 g, 4 mmol) was added and the mixture was allowed toreact at room temperature for 24 h. The solvent was evaporated and theresidue was purified by chromatography (silica, CH₂ Cl₂ :MeOH, 97:3) togive 102 mg (9%) of the title compound.

(¹ H-NMR, 300 MHz, CDCl₃). 1.40 (s, 3H), 1.45 (s, 3H), 2.55 (s, 3H),5.35 (m, 1H), 7.10 (dd, 1H) 7.86 (d, 2H), 7.95 (d, 1H), 8.20 (m, 3H).

Example XXII

3-Methyl-2-phenylpyrrolo[2,3 -b]pyridine

A mixture of 1-hydrazinopyridine (21.8 g, 20 mmol) and propiophenone(29.3 g, 22 mmol) in 160 ml 95% EtOH was refluxed for 3 h. Evaporationof the solvent afforded a quantitative yield of the correspondinghydrazone.

(DI-MS, E1 at 70 eV) m/z 225 (8), 196 (100), 148 (15).

The residue was dissolved in 200 ml DEG, deaerated and violentlyrefluxed in a nitrogen atmosphere for 4 h. The reaction mixture wasallowed to cool overnight and poured into 1000 ml H₂ O. The precipitatedproduct was collected and recrystallized from EtOH affording 18.4 g(44%) of the desired product.

(¹ H-NMR, 500 MHz, CDCl₃). 2.49 (s, 3H), 7.07 (dd, 1H), 7.42 (t, 1H),7.55 (t, 2H), 7.73 (d, 2H), 7.91 (d, 1H), 8.21 (d, 1H), 11.38 (b, 1H).

Example XXIII

3-Methyl-2-(p-methylphenyl)pyrrolo[2,3-b]pyridine

The title compound was prepared on a 10 mmol scale following theprocedure described in example XXII above. Yield 0.9 g (4%), (DI-MS, E1at 70 eV of the hydrazone) m/z 239 (5), 210 (100), 148 (12).

(¹ H-NMR, 500 MHz, CDCl₃ of the title compound). 2.45 (s, 3H), 2.47 (s,3H), 7.08 (dd, 1H), 7.34 (d, 2H), 7.59 (d, 2H), 7.89 (dd, 1H), 8.23 (dd,1H), 10.6 (b, 1H).

Example XXIV

2-(p-Methoxyphenyl)-3-methyl-pyrrolo[2,3-b]pyridine

The title compound was prepared on a 20 mmol scale following theprocedure described in example XXII above. Yield 6.0 g (13%). (DI-MS, E1at 70 eV of the hydrazone) m/z 255 (8), 226 (100), 211 (12).

(¹ H-NMR, 500 MHz, CDCl₃ of the title compound). 2.45 (s, 3H), 3.90 (s,3H), 7.06 (m, 3H), 7.63 (d, 2H), 7.87 (dd, 1H), 8.12 (dd, 1H), 10.7 (b,1H).

Example XXV

Preparation of 5-fluoro-2hydrazinopyridine

A mixture of 2-chloro-5-fluropyridine (5 g, 0.038 mol) and hydrazinemonohydrate (15 ml, 0.32 mol) in n-propanol (40 ml) in a tefloncontainer was purged with argon and heated in a stainless steel bomb at200° C. for 19 h (magnetic stirring). Evaporation of solvent and excesshydrazine monohydrate in vacuo gave a solid residue (5.9 g) which wasdissolved in sodium bicarbonate solution (5%) and extracted with 6×50 mlethyl acetate. The combined extracts were dried over anhydrous Na₂ SO₄,filtered and evaporated to give an oil (2.9 g) which proved difficult topurify and was therefore used as such in the next step. The crudeproduct consisted of a ternary mixture of the desired product,2-chloro-5-hydrazinopyridine, and 5-hydrazinopyridine.

(¹ H-NMR, 500 MHz, DMSO-d₆). 6.73 (dd, 1H, J₁ 9 Hz, J₂ 3.5 Hz), 7.41(td, 1H, J₁ 9.5 Hz, J₂ 3 Hz), 7.95 (d, 1H, J₁ 3 Hz)

Example XXVI

Preparation of 5-fluoro-2-methyl-3-methyltiopyrrolo[2,3-b ]pyridine

A solution of crude 5-fluoro-2hydrazinopyridine (6.7 g, max. 0.053 mol)and (α-methyltio)acetone (6.04 g, 0.058 mol) in ethanol (99.5%, 15 ml)was heated to reflux for a couple of minutes and then evaporated underreduced pressure to afford an oil (11.5 g) . A solution of the oil indiethylene glycol (50 ml) was heated at reflux temperature under argonfor 8 h. The reaction mixture was cooled to room temperature, dilutedwith Na₂ CO₃ solution (10%, 200 ml), and extracted with diethyl ether(200 and methylene chloride (2×200 ml). The combined extracts were driedover anhydrous Na₂ SO₄ and evaporated in vacuo to give an oil from whichthe title compound (0.22 g, 2%, two steps) was isolated by flashchromatography (SiO₂ /MeOH:CH₂ Cl₂ 0, 1, and 2%).

MS m/z (relative intensity) 196 (100, M⁺), 181 (100), 137 (58).

Example XXVII

Preparation of 5-fluoro-2-methylpyrrolo[2,3-b]pyridine

Raney-Ni (10 g wet alloy, Aldrich W2, was washed with 10×50 ml deionizedwater and 5×40 ml dioxane) was suspended in a solution of5-fluoro-2-methyl-3-methyltiopyrrolo[2,3-b]pyridine (0.5 g, 2.5 mmol) indioxane (50 ml). The reaction mixture was stirred under hydrogen for 43h. More Raney-Ni (5 g wet) was added and stirring under hydrogen wascontinued over a weekend (69 h). Filtration through Celite andevaporation gave 0.24 g crude product. Additional crude product (0.48 g)was isolated by Soxhlet extraction of the Raney-Ni. The crude prucuctwas used in the next step without prior purification.

MS m/z (relative intensity) 150 (75, M⁺), 149 (100), 122 (15).

Example XXVIII

Preparation of 3-(cyanomethyl)-5-fluoro-2-methylpyrrolo [2 3-b]pyridine

Mannich reagent (0.8 ml, prepared according to Liebigs (1971) Ann.Chem., 743, 95-111) was added under stirring to pre-cooled (-78° C.)5-fluoro-2-methylpyrrolo[2,3-b]pyridine (0.33 g, 2.2 mmol) under argon.The flask containing the reaction mixture was then placed in an ice bathand stirring was continued to give a white suspension. The ice lumpsmelted within 2 h and the resulting water bath was allowed attain roomtemperature. After 24 h almost all suspension had dissolved. Thereaction mixture was cooled in an ice bath, diluted with deinionizedwater (8 ml) and extracted with diethyl ether (2×5 ml) to remove someremaining starting material and a by-product (propably the correspondingMannich dimer). Sodium cyanide (1.08 g, 0.022 mol) was added to thewater phase, assumed to contain3-(dimethylaminomethyl)-5-fluoro-2-methylpyrrolo[2,3 -b]pyridine, andthe resulting solution was refluxed for 2 h to afford a suspension whichwas isolated by filtration. Purification by flash chromatography(SiO.sub. 2 /CH₂ Cl₂ :MeOH 19:1) gave 0.28 g (67%, two steps) of3-(cyanomethyl)-5-fluoro-2-methylpyrrolo[2,3-b]pyridine.

MS m/z (relative intensity) 189 (100, M⁺), 188 (97), 174 (83), 163 (55),162 (35), 147 (18), 121 (19).

Example XXIX

Preparation of 5-bromo-2-hydrazinopyridine

Starting from 2,5-dibromopyridine the title compound was prepared in thesame fashion as 5-chloro-2-hydrazinopyridine. (¹ H-NMR, 300 MHz, CDCl₃).3.78 (br s, 2H), 5.83 (br s, 1H), 6.65 (d, 1H, J 9 Hz), 7.54 (dd, 1H, J₁9 Hz, J₂ 2.5 Hz), 8.14 (d, 1H, J 2.5).

Example XXX

Preparation of 5-bromo-3-methyl-2-phenylpyrrolo[2.3-b]pyridine

5-Bromo-2-hydrazinopyridine (15.6 g, 0.083 mol) and propiophenone (11.1ml) was heated at 90° C. (steam bath) for 30 min. Then toluene (100 ml)was added and the resulting solution was refluxed for 2 h to removewater by azeotropic distillation (Dean Stark apparatus). Evaporation ofsolvent gave 26.4 g of crude product, assumed to be the desiredhydrazone. Crude hydrazone (3.02 g) was dissolved in diethylene glycol(30 ml) and heated at 245° C. under argon for 24 h. The reaction mixturewas poored crushed ice and extracted with methylene chloride. Dryingover MgSO₄ and evaporation of solvent left a tary residue which wastriturated with diethyl ether to produce 0.84 g (30%) of a brownish,semi-crystalline product.

(¹ H-NMR, 300 MHz, DMSO-d₆). 2.50 (s, 3H), 7.41 (t, 1H, J 7 Hz), 7.52(t, 2H, J 7 Hz), 7.71 (d, 2H, J 7 Hz), 8.23 (m, 2H).

Example XXXI

Preparation of 2-phenylpyrrolo[2,3-b]pyridine

A mixture of acetophenone (28.2 g, 0.24 mol) and 2-hydrazinopyridine(25.7 g, 0.24 mol) was heated on a steam bath for 0.5 h. Toluene (200ml) was added to give a solution which was refluxed for 2 h to removewater by azeotropic distillation (Dean Stark apparatus). Evaporation ofsolvent gave 55.4 g of crude product, assumed to be the desiredhydrazone. The crude hydrazone was purified by distillation (Vigreuxapparatus) to give a yellow oil (38.4 g, 77%). Fresh hydrazone (18 g,0.085 mol) was dissolved in tetraethylene glycol (180 ml) and refluxedunder argon for 6 h. The reaction mixture was cooled, diluted withdiethyl ether (250 ml) and water (250 ml) under stirring. The phaseswere separated and the water phase was reextracted with diethyl ether(200 ml). The combined ether phases were dried over anhydrous sodiumsulphate, filtered and evaporated to leave a black oil (14.9 g) whichwas further purified by kugel-rohr distillation, flash chromatography(SiO₂ /MeOH:CH₂ Cl₂, first none methanol, then gradually more methanolto increase mobility) and recrystallization (methylene chloride) toafford 1.5 g of pure 2-phenylpyrrolo[2,3 -b]pyridine.

MS m/z (relative intensity) 195 (15, M+1), 194 (100, M⁺), 193 (20), 166(12), 139 (10), 97 (21), 91 (18), 84 (11).

Example XXXII

Preparation of 3-(cyanomethyl)-2-phenylpyrrolo[2.3-b]pyridine

Aqueous formaldehyde (36%, 1.7 ml) was cooled (ice bath), then aceticacid (3 ml) and aqueous dimethylamine (40%, 2.5 ml) were added. Thatsolution was kept at 0° C. for 30 minutes before part of it (2.6 ml) wastransfered to a precooled (-78° C.) flask containing2-phenylpyrrolo[2,3-b]pyridine under argon. After 5 min the temperaturewas changed to 0° C. (ice bath) and it was allowed to reach roomtemperature within 2 h. Stirring of the resulting suspension wasmaintained for 110 h. Re-cooling to 0° C. and addition of cooleddeionized water (25 ml) and diethyl ether (7 ml) under stirring gave twophases which were separated. The organic phase was discarded since itwas assumed to contain some remaining starting material and some Mannichdimer.

Sodium cyanide (3.6 g) was added to the water phase which was assumed tocontain 3-(dimethylaminomethyl)-2-phenylpyrrolo [2,3-b]pyridine. Themixture was refluxed for 3 h without any noticeable change in TLCapprearance (SiO₂ /CH₂ Cl₂ :MeOH 19:1), indicating that the Mannich basewas unchanged. 3-(Dimethylaminomethyl)-2-phenylpyrrolo[2,3-b]pyridinewas recovered from the reaction mixture by the following procedure.Water (25 ml) was added, solid material was filtered off, and filtratewas extracted with methylene chloride. The major part of the Mannichbase was isolated from the filter cake by repeated washing withmethylene chloride. The combined washings (3×100 ml), containing thesparingly soluble Mannich base, was dried and evaporated untilprecipitation just started. The saturated solution was loaded on a flashchromatography column (SiO₂ /CH₂ Cl₂, prepared in CH₂ Cl₂ :MeOH 9:1).Recovered 3-(dimethylaminomethyl)-2-phenylpyrrolo[2,3 -b]pyridine (1.26g, 68%) was isolated by eluting with methylene chloride methanolmixtures (1.500 ml CH.sub. 2 Cl₂ ; 2.500 ml MeOH:CH₂ Cl₂ 2:98;3.500 mlMeOH:CH₂ Cl₂ 4:96;4.500 ml MeOH:CH₂ CL₂ 8:92).

Ethyl iodide (1.94 g, 0.012 mol) was added to a solution of recoveredMannich base (1.25 g, 5 mmol) in methanol (10 ml). The solution wasstirred under argon for 1.5 h. Then a solution of potassium cyanide(0.81 g, 0.012 mol) in deionized water (1.8 ml ) was added. The reactionmixture was heated to reflux for 1 h. Solvents were evaporated and theresulting residue was diluted with water (10 ml) and extracted withethyl acetate (3×10 ml). The combined extracts were dried (MgSO₄) andevaporated in vacuo to give a solid which was purified by flashchromatography (SiO₂ /CH₂ Cl₂, elution with increasing amounts ofmethanol, se above) leaving pure title compound (0.85 g, 73%).

(¹ H-NMR, 300 MHz, DMSO-d₆). 4.18 (s, 2H), 7.17 (q, 1H, J₁ 7.5 Hz, J₂4.5 Hz), 7.43-7.51 (m, 1H), 7.54-7.60 (m, 2H), 7.67-7.71 (m, 2H), 8.14(dd, 1H, J₁ 7.5 Hz, J₂ 1.5 Hz), 8.3 0 (dd, 1H, J₁ 4.5 Hz, J₂ 1.5 Hz).

Example XXXIII

Preparation of 3-(carbamoylmethyl)-2-phenylpyrrolo[2.3-b]pyridine

3-(Cyanomethyl)-2-phenylpyrrolo[2,3-b]pyridine (0.37 g, 1.39 mmol),powdered KOH (0.82 g), and t-butanol (5 ml) were heated to reflux underargon for 3 h. The reaction mixture was then cooled to room temperatureand diluted with deionized water (6.5 ml) to give a precipitate. Thesuspension was extracted with methylene chloride and filtered. Thefilter cake consisted of pure title compound.

(¹ H-NMR, 300 MHz, DMSO-d₆). 3.59 (s, 2H), 6.96-7.03 (m, 2H), 7.33-7.51(m, 4H), 7.79-7.84 (m, 2H), 8.13 (dd, 1H, J₁ 7.5 Hz, J₂ 1.5 Hz ), 8.30(dd, 1H, J₁ 4.5 Hz, J₂ 1.5 Hz).

For clinical use the compounds of the invention are formulated intopharmaceutical formulations for oral, rectal, parenteral or other modeof administration. The pharmaceutical formulation contains a compound ofthe invention in combination with a pharmaceutically acceptable carrier.The carrier may be in the form of a solid, semi-solid or liquid diluent,or a capsule. These pharmaceutical preparations are a further object ofthe invention. Usually the amount of active compounds is between 0.1-95%by weight of the preparation, between 0.2-20% by weight in preparationsfor parenteral use and between 1 and 50% by weight in preparations fororal administration. In the preparation of pharmaceutical formulationscontaining a compound of the present invention in the form of dosageunits for oral administration the compound selected may be mixed with asolid, powdered carrier, such as lactose, saccharose, sorbitol,mannitol, starch, amylopectin, cellulose derivatives, gelatin, oranother suitable carrier, as well as with lubricating agents such asmagnesium stearate, calcium stearate, sodium steryl fumarate andpolyethylene glycol waxes. The mixture is then processed into granulesor pressed into tablets. Soft gelatine capsules may be prepared withcapsules containing a mixture of the active compound or compounds of theinvention, vegetable oil, fat, or other suitable vehicle for softgelatine capsules. Hard gelatine capsules may contain granules of theactive compound. Hard gelatine capsules may also contain the activecompound in combination with a solid powdered carrier such as lactose,saccharose, sorbitol, mannitol, potato starch, corn starch, amylopectin,cellulose derivatives or gelatine.

Dosage units for rectal administration may be prepared in the form ofsuppositories which contain the active substance mixed with a neutralfat base, or they may be prepared in the form of a gelatine rectalcapsule which contains the active substance in a mixture with avegetable oil, paraffin oil or other suitable vehicle for gelatinerectal capsules, or they may be prepared in the form of a ready-mademicro enema, or they may be prepared in the form of a dry micro enemaformulation to be reconstituted in a suitable solvent just prior toadministration.

Liquid preparations for oral administration may be prepared in the formof syrups or suspensions, e.g. solutions or suspensions containing from0.2% to 20% by weight of the active ingredient and the remainderconsisting of sugar or sugaralcohols and a mixture of ethanol, water,glycerol, propylene glycol and polyethylene glycol. If desired, suchliquid preparations may contain colouring agents, flavouring agents,saccharine and carboxymethyl cellulose or other thickening agent. Liquidpreparations for oral administration may also be prepared in the form ofa dry powder to be reconstituted with a suitable solvent prior use.

Solutions for parenteral administration may be prepared as a solution ofa compound of the invention in a pharmaceutically acceptable solyen,preferably in a concentration from 0.1% to 10% by weight. Thesesolutions may also contain stabilizing unit dose ampoules or vials.Solutions for parenteral administration may also be prepared as a drypreparation to by reconstituted with a suitable solvent extemporaneouslybefore use.

The typical daily dose of the active substance varies within a widerange and will depend on various factors such as for example theindividual requirement of each patient, the route of administration andthe disease. In general, oral and parenteral dosages will be in therange of 5 to 500 mg per day of active substance.

Pharmaceutical formulations containing a compound of the invention asactive ingredient are illustrated in the following examples.

Example A. Syrup.

A syrup containing 1% (weight per volume) of active substance wasprepared from the following ingredients:

    ______________________________________                                        Compound according to Example 49                                                                        1.0    g                                            Sugar, powder             30.0   g                                            Saccharine                0.6    g                                            Glycerol                  5.0    g                                            Flavouring agent          0.05   g                                            Ethanol 96%               5.0    g                                            Distilled water q.s. to a final volume of                                                               100    ml                                           ______________________________________                                    

Sugar and saccharine were dissolved in 60 g of warm water. After coolingthe acid addition salt was dissolved in the sugar solution and glyceroland a solution of flavouring agents dissolved in ethanol were added. Themixture was diluted with water to a final volume of 100 ml.

The above given active substance may be replaced with otherpharmaceutically acceptable acid addition salts.

Formulation B. Tablets

A tablet containing 50 mg of active compound was prepared from thefollowing ingredients:

    ______________________________________                                        I      Compound according to Example 49                                                                      500 g                                                 Lactose                 700 g                                                 Methyl cellulose        6 g                                                   Polyvinylpyrrolidone cross-linked                                                                     50 g                                                  Magnesium stearate      15 g                                                  Sodium carbonate        6 g                                                   Distilled water         q.s.                                           II     Hydroxypropyl methylcellulose                                                                         36 g                                                  Polyethylene glycol     9 g                                                   Colour Titanium dioxide 4 g                                                   Purified water          313 g                                          ______________________________________                                    

I Compound according to example 49, powder, was mixed with lactose andgranulated with a water solution of methyl cellulose and sodiumcarbonate. The wet mass was forced through a sieve and the granulatedried in an oven. After drying, the granulate was mixed withpolyvinylpyrrolidone and magnesium stearate. The dry mixture was pressedinto tablet cores (10,000 tablets), each tablet containing 50 mg ofacrive substance, in a tabletting machine using 7 mm diameter punches.

II A solution of hydroxypropyl methylcellulose and polyethylene glycolin purified water was prepared. After dispersion of titanium dioxide thesolution was sprayed onto the tablets I in an Accela Cora®, Manestycoating equipment. A final tablet weight of 175 mg was obtained.

Formulation C. Solution for intravenous administration

A parenteral formulation for intravenous use, containing 4 mg of activecompound per ml, was prepared from the following ingredients:

    ______________________________________                                        Compound according to Example 49                                                                       4      g                                             Polyethylene glycol 400 for injection                                                                  400    g                                             Disodium hydrogen phosphate                                                                            q.s.                                                 Sterile water to a final colume of                                                                     1.000  ml                                            ______________________________________                                    

Compound according to Example 49 was dissolved in polyethylene glycol400 and 550 ml of water was added. pH of the solution was brought to pH7.4 by adding a water solution of disodium hydrogen phosphate and waterwas added to a final volume of 1000 ml. The solution was filteredthrough a 0.22 μm filter and immediately despensed into 10 ml sterileampoules. The ampoules were sealed.

Biological tests

A. Inhibiting effect in vitro on acid secretion in isolated rabbitgastric glands was measured as described by Berglindh et al. (1976),Acta physiol. scand., 97, 401-414.

Most of the compounds in Table 1 had an IC₅₀ value in the range of0,2-100 μM.

B. Inhibiting effect in vivo on acid secretion in conscious female ratwas measured according to the following method:

Female rats of the Sprague-Dawley strain were used. They were equippedwith cannulated fistulae in the stomach (lumen) and the upper part ofthe duodenum, for collection of gastric secretions and administration oftest substances, respectively. A fourteen days recovery period aftersurgery was allowed before testing commenced.

Before secretory tests, the animals were deprived of food but not waterfor 20 h. The stomach was repeatedly washed through the gastric cannulawith tapwater (37° C.), and 6 ml of Ringer-Glucose given s.c. Acidsecretion was stimulated with infusion during 3.0 h (1,2 ml/h, s.c.) ofpentagastrin and carbachol (20 and 110 nmol/kg h, respectively), duringwhich time gastric secretions were collected in 30-min fractions. Testsubstances or vehicle were given iv or id at 60 min after starting thestimulation, in a volume of 1 ml/kg. Gastric juice samples were titratedto pH 7.0 with NaOH, 0.1 mol/L, and acid output calculated as theproduct of titrant volume and concentration. Further calculations werebased on group mean responses from 4-5 rats. The acid output during theperiods after administration of test substances or vehicle wereexpressed as fractional responses, setting the acid output in the 30-minperiod preceding administration to 1.0. Percentage inhibition wascalculated from the fractional responses elicited by test compound andvehicle. ED₅₀ -values were obtained from graphical interpolation on logdose-response curves, or estimated from single-dose experiments assuminga similar slope for all dose-response curves. The results are based ongastric acid secretion during two hours after drug/vehicleadministration.

The compound according to Example 49 had after id administration an ED₅₀value of 2 μmol/kg.

The compound according to Example 63 had after iv administration an ED₅₀value of 1.3 μmol/kg.

What we claim is:
 1. A compound of the formula I ##STR31## or apharmaceutically acceptable salt thereof, wherein X represents ##STR32##or --CH₂ --; R¹ represents H, lower alkyl, CH₂ --O--R⁷ ' halogen, phenylor phenyl substituted with (1-6c) alkyl, (1-6c) alkoxy, (1-6c) acyl,halogen, CF₃, CN, NH₂, NO₂, or (1-6c) alkoxycarbonyl;R² represents H,lower alkyl, CH₂ CN, ##STR33## halogen, O--R⁸, ##STR34## S--CN, CH₂ OH,CH₂ C.tbd.CH, CF₃,CH₂ NC or NH₂ ; R³ represents H, lower alkyl, CF₃,O--R⁹, NH₂, lower alkylamino, di-lower alkylamino, halogen, CN,##STR35## S--R¹⁰, or NHCOR¹⁰ ; R⁴ and R⁵, which are the same ordifferent, represent H, lower alkyl, CN, halogen, O--R¹¹, NO₂, NH₂,lower alkylamino, di-lower alkylamino, S--R¹², NHCOR¹³, ##STR36## R⁶,R⁷, R⁸, R⁹, R¹¹ and R¹³ which are the same or different, represent H orlower alkyl; R¹⁰ represents lower alkyl or phenyl lower alkyl; R¹² andR¹⁴ which are the same or different represent lower alkyl; R¹⁵represents H, lower alkyl, OH or lower alkoxy; provided that R¹ and R²are not simultaneously H.
 2. A compound according to claim 1 wherein Xis --CO--, ##STR37## or --CH₂ -- and R⁶ is H or (1-6C) alkyl.
 3. Acompound according to claim 1 wherein R¹ is (1-6C) alkyl, optionallysubstituted phenyl, --CH₂ OR⁷, or halogen, wherein is H or (1-6C) alkyl.4. A compound according to claim 1 wherein R² is H, (1-6C) alkyl, --CH₂C.tbd.CH, --CH₂ OH, --CH₂ CN, --CH₂ CONH₂, --CH₂ NC, --NH₂, ##STR38##--SCN, halogen, or --CF₃.
 5. A compound according to claim 1 wherein R³is H, (1-6C) alkyl, --OR⁹, --NH₂, (1-6C)alkyl-amino (1-6C)dialkylamino,--CN, --SR¹⁰, halogen --CF₃, or --NHCOR¹⁰, wherein R⁹ is H or(1-6C)alkyl, and R¹⁰ is (1-6C)alkyl or phenyl-(1-6C)-alkyl.
 6. Acompound according to claim 1 wherein R⁴ and R⁵ are the same ordifferent and selected from H, (1-6C)alkyl, --CN, halogen, --OR¹¹,--NO₂, --NH₂, (1-6C)alkylamino, (1-6C)dialkylamino, --SR¹², --NHCOR¹³,--CF₃, or --COR¹⁵, wherein R¹¹ is H or (1-6C)alkyl, R¹² is (1-6C)alkyl,R¹³ is H or (1-6C) alkyl and R¹⁵ is H, (1-6C)alkyl, OH, or (1-6C)alkoxy.
 7. A compound according to claim 1 wherein X is --CO--, --CH, or--CH₂ --;R¹, is (1-6C)alkyl, optionally substituted phenyl, --CH₂ OR⁷,or halogen, and R⁷ is H or (1-6C)alkyl; R² is H, (1-6C)alkyl, --CH₂C.tbd.CH, --CH₂ OH, --CH₂ CN, --CH₂ CONH₂, --CH₂ NC, --NH₂, ##STR39##--SCN, halogen, or --CF₃ ; R³ is H, (1-6)alkyl, --OR⁹, --NH₂,(1-6C)alkylamino, (1-6C)dialkylamino, --CN --SR¹⁰, halogen, --CF₃, or--NHCOR¹⁰, and R⁹ is H: or (1-6C)alkyl, and R¹⁰ is (1-6C)alkyl, orphenyl-(1-6C)-alkyl; and R⁴ and R⁵ are the same or different andselected from H, (1-6C)alkyl, --CN, halogen, --OR¹¹, --NO₂, --NH₂,(1-6C)alkylamino, (1-6C)dialkylamino, --SR¹², --NHCOR¹³, --CF₃, or--COR¹⁵, wherein R¹¹ is H or (1-6C)alkyl, R¹² is (1-6C)alkyl, R¹³ is Hor (1-6C)alkyl, and R¹⁵ is H, (1-6C)alkyl, OH, or (1-6C)alkoxy.
 8. Acompound according to claim 1 wherein X is --CO--, --CH(OH)--,--CH(OCH₃)--, --CH(OC₂ H₅)--, or --CH₂ --.
 9. A compound according toclaim 1 wherein R¹ is CH₃, C₂ H₅, CH(CH₃)₂, (CH₂)₂ CH₃, Cl, Br, orphenyl.
 10. A compound according to claim 1 wherein R² is H, CH₃, C₂ H₅,CH₂ CN, CH₂ CONH₂, F, Cl, Br, --SCN, CH₂ OH, CH₂ C.tbd.CH, CF₃ or CH₂NC.
 11. A compound according to claim 1 wherein R³ is H, CH₃, C₂ H₅,CH(CH₃)₂,(CH₂)₂ CH₃,CF₃, OH, OCH₃, OC₂ H₅, OCH(CH₃)₂, NH₂, NHCH₃, NHC₂H₅, N(CH₃)₂, N(C₂ H₅)₂, F, Cl, Br, SCH₃, SC₂ H₅, ##STR40## or NHCOCH₃.12. A compound according to claim 1 wherein R⁴ and R⁵ which are the sameor different, are selected from H, CH₃, C₂ H₅, CH(CH₃)₂, F, Cl, Br, OH,OCH₃, OC₂ H₅, OCH(CH₃)₂, NO₂, NH₂, NHCH₃, NHC₂ H₅, N(CH₃)₂, N(C₂ H₅)₂,SCH₃, or CF₃.
 13. A compound according to claim 1 wherein X is --CO--,--CH(OH)--, CH(OCH₃)--, --CH(OC₂ H₅)--, or --CH₂ --;R¹ is CH₃, C₂H₅,CH(CH₃)₂, (CH₂)₂ CH₃, Cl, Br, or phenyl; R² is H, CH₃, C₂ H₅, CH₂ CN,CH₂ CONH₂, F, Cl, Br, --SCN,CH₂ OH,CH₂ C.tbd.CH,CF₃, or CH₂ NC; R³ is H,CH₃, C₂ H₅, CH(CH₃)₂, (CH₂)₂ CH₃, CF₃, OH, OCH₃, OC₂ H₅, OCH(CH₃)₂, NH₂,NHCH₃, NHC₂ H₅, N(CH₃)₂, N(C₂ H₅)₂, F, Cl, Br, SCH₃, SC₂ H₅, ##STR41##or NHCOCH₃ ; and R⁴ and R⁵ are the same or different and selected fromH, CH₃, C₂ H₅, CH(CH₃,)₂, F, Cl, Br, OH, OCH₃, OC₂ H₅, OCH(CH₃)₂, NO₂,NH₂, NHCH₃, NHC₂ H₅, N(CH₃)₂, N(C₂ H₅)₂, SCH₃, or CF₃.
 14. A compoundaccording to claim 1 of the formula ##STR42## and pharmaceuticallyacceptable salts thereof.
 15. A compound according to claim 1 of theformula ##STR43## and pharmaceutically acceptable salts thereof.
 16. Acompound according to claim 1 of the formula ##STR44## andpharmaceuticallly acceptable salts thereof.
 17. A compound according toclaim 1 of the formula ##STR45## and pharmaceutically acceptable saltsthereof.
 18. A compound according to claim 1 of the formula ##STR46##and pharmaceutically acceptable salts thereof.
 19. A compound accordingto claim 1 of the formula ##STR47## and pharmaceutically acceptablesalts thereof.
 20. A compound according to claim 1 of the formula##STR48## and pharmaceutically acceptable salts thereof.
 21. A compoundaccording to claim 1 of the formula ##STR49## and pharmaceuticallyacceptable salts thereof.
 22. A compound according to claim 1 of theformula ##STR50## and pharmaceutically acceptable salts thereof.
 23. Acompound according to claim 1 of the formula ##STR51## andpharmaceutically acceptable salts thereof.
 24. A compound according toclaim 1 of the formula ##STR52## and pharmaceutically acceptable saltsthereof.
 25. A compound according to claim 1 of the formula ##STR53##and pharmaceutically acceptable salts thereof.
 26. A compound accordingto claim 1 of the formula ##STR54## and pharmaceutically acceptablesalts thereof.
 27. A compound according to claim 1 of the formula##STR55## and pharmaceutically acceptable salts thereof.
 28. A compoundaccording to claim 1 of the formula ##STR56## and pharmaceuticallyacceptable salts thereof.
 29. A compound according to claim 1 of theformula ##STR57## and pharmaceutically acceptable salts thereof.
 30. Acompound according to claim 1 of the formula ##STR58## or apharmaceutically acceptable salt thereof.
 31. A pharmaceuticalcomposition containing as active ingredient a compound according toclaim
 1. 32. A method for inhibiting gastric acid secretion whichcomprises administering to mammals and man a compound as defined inclaim
 1. 33. A method for the treatment of gastrointestinal inflammatorydiseases in mammals and man which comprises administering a compound asdefined in claim 1.